###Harrold, Marc W Zavod, Robin M PDF

Robin M.
Zavod, PhD
Editor-in-Chief, Currents in Pharmacy Teaching
and Learning
Professor of Pharmaceutical Sciences
Midwestern University Chicago College of
Pharmacy
Downers Grove, Illinois
Marc W. Harrold, PhD

Professor of Medicinal Chemistry
Duquesne University Mylan School of Pharmacy
Pittsburgh, Pennsylvania
Any correspondence regarding this publication should be sent to the publisher, American Society of
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ISBN: 978-1-58528-464-1
10 9 8 7 6 5 4 3 2 1
DEDICATION
To our students, whose

creative problem solving
has not only taunted and
teased us, but has also
inspired us to develop
review questions that
provide meaningful
guidance during the
structure evaluation
journey.
TABLE OF CONTENTS
Preface .......................................................................................................................................................................................... vii

Acknowledgments.......................................................................................................................................................................... ix
PART I QUESTIONS
Section 1 General Self Assessment
1.1 Functional Group Characteristics and Roles........................................................................................................................ 1
1.2 Identifying Acidic and Basic Functional Groups................................................................................................................... 7
1.3 Solving pH/pKa Problems................................................................................................................................................... 11
1.4 Salts and Solubility............................................................................................................................................................ 13
1.5 Drug Binding Interactions.................................................................................................................................................. 17
1.6 Stereochemistry and Drug Action...................................................................................................................................... 21
1.7 Drug Metabolism............................................................................................................................................................... 23
Section 2 Whole Molecule Drug Evaluation

1.8 Aliskiren............................................................................................................................................................................ 27
1.9 Aripiprazole....................................................................................................................................................................... 31
1.10 Cefprozil............................................................................................................................................................................ 35
1.11 Cetirizine........................................................................................................................................................................... 39
1.12 Chlorpropamide and Other Sulfonylureas ......................................................................................................................... 41
1.13 Dabigatran Etexilate.......................................................................................................................................................... 45
1.14 Fenofibrate and Gemfibrozil.............................................................................................................................................. 47
1.15 Fluvoxamine...................................................................................................................................................................... 51
1.16 Haloperidol........................................................................................................................................................................ 55
1.17 Hydrocortisone.................................................................................................................................................................. 57
1.18 Levothyroxine.................................................................................................................................................................... 61
1.19 Lidocaine........................................................................................................................................................................... 65
1.20 Montelukast and Zafirlukast.............................................................................................................................................. 69
1.21 Phenobarbital and Other Barbiturates............................................................................................................................... 71
1.22 Pravastatin and Fluvastatin............................................................................................................................................... 73
1.23 Quinapril........................................................................................................................................................................... 75
1.24 Rivastigmine...................................................................................................................................................................... 79
1.25 Sitagliptin.......................................................................................................................................................................... 83
1.26 Sorafenib........................................................................................................................................................................... 87
1.27 Zanamivir and Oseltamivir ............................................................................................................................................... 91
PART 2 ANSWERS
2.1 Functional Group Characteristics and Roles...................................................................................................................... 95
2.2 Identifying Acidic and Basic Functional Groups................................................................................................................. 99
TABLE OF CONTENTS
2.3 Solving pH/pKa Problems................................................................................................................................................ 105

2.4 Salts and Solubility......................................................................................................................................................... 109
2.5 Drug Binding Interactions............................................................................................................................................... 113
2.6 Stereochemistry and Drug Action................................................................................................................................... 117
2.7 Drug Metabolism ........................................................................................................................................................... 123

2.8 Aliskiren......................................................................................................................................................................... 129
2.9 Aripiprazole.................................................................................................................................................................... 137
2.10 Cefprozil......................................................................................................................................................................... 143
2.11 Cetirizine........................................................................................................................................................................ 149
2.12 Chlorpropamide and Other Sulfonylureas ...................................................................................................................... 153
2.13 Dabigatran Etexilate....................................................................................................................................................... 159
2.14 Fenofibrate and Gemfibrozil........................................................................................................................................... 165
2.15 Fluvoxamine................................................................................................................................................................... 169
2.16 Haloperidol..................................................................................................................................................................... 173
2.17 Hydrocortisone............................................................................................................................................................... 177
2.18 Levothyroxine................................................................................................................................................................. 183
2.19 Lidocaine........................................................................................................................................................................ 189
2.20 Montelukast and Zafirlukast........................................................................................................................................... 193
2.21 Phenobarbital and Other Barbiturates............................................................................................................................ 199
2.22 Pravastatin and Fluvastatin............................................................................................................................................ 205
2.23 Quinapril........................................................................................................................................................................ 211
2.24 Rivastigmine................................................................................................................................................................... 217
2.25 Sitagliptin....................................................................................................................................................................... 223
2.26 Sorafenib........................................................................................................................................................................ 227
2.27 Zanamivir and Oseltamivir ............................................................................................................................................ 233
INDEX .................................................................................................................................................................................... 239

vii
PREFACE
If our suspicions are correct, you’ve heard the phrases, “Keep up the good work—you’ll get better with
practice!” and “Keep practicing and you’ll see that it gets easier.” Regardless of whether it is a coach,
teacher, clergy member, scout leader, friend, or family member providing this encouragement, the person
receiving this advice is likely learning a new skill, technique, or language. With practice, soccer goals
are scored, training wheels are removed, piano and ballet recitals are executed, and tents are pitched.
Through self assessment, one is able to both relish the “victory,” as well as consider how he or she could
have improved.
When learning a new language, another common expression is, “If you don’t use it, you’ll lose it.” The
Basic Concepts in Medicinal Chemistry textbook served to lay the “language” foundation for drug struc-
ture evaluation. Whereas written/spoken language is based on phonemic awareness and phonetics, the
language of medicinal chemistry is based on functional group identification and evaluation. These func-
tional groups “speak” to biological targets via key binding interactions, with stimulation or inhibition of
key physiological and biochemical processes as the response. Mastery of this language will help facilitate
a learner’s journey into understanding structure activity relationships—the next level of structure evalua-
tion.
The Basic Concepts in Medicinal Chemistry chapters discussed physicochemical properties, provided clini-
cally relevant examples and, through the review problems, offered an opportunity to practice new struc-
ture evaluation skills. With all of the variations of practice makes perfect ringing in our ears, Marc and I
agreed that one way to help cement the concepts in the textbook chapters is to offer learners a chance
to engage in self assessment. Better yet, we knew that the next step was to put all of the functional
group pieces together to support whole molecule evaluation.
This workbook is split into two sections with two goals in mind. Our first goal is to help the learner
reinforce his or her foundational knowledge. Additional practice problems focus on the following eight
fundamental types of evaluation:
1. Identification of functional groups that contribute to water solubility and those that contribute
to lipid solubility and the need for a balance between the two
2. The role of electron withdrawing and donating functional groups on adjacent atoms and func-
tional groups
3. Identification of acidic and basic functional groups and related ionization under physiologically
relevant conditions
4. Use of the Henderson-Hasselbalch equation to solve both qualitative and quantitative pH and pKa
problems
5. Formation of inorganic and organic salts of specific functional groups and the value of those salts
6. Interaction chemistry between a drug molecule and its biological target for drug action
7. Spatial orientation of functional groups
8. Metabolic routes of drug activation, inactivation, and/or elimination
Our second goal, and the natural next step in the learning process, is to have the learner put all of his or
her evaluation skills together and fully assess all of the functional groups within a given drug molecule.
Twenty contemporary drugs that span an equivalent number of drug classes were selected as representa-
tive models for whole molecule evaluation. Section questions challenge the learner to anticipate what
could happen to a drug molecule (e.g., what metabolites could form), as well as to provide an explana-
tion for an observed pharmacodynamic (e.g., mechanism of action) or pharmacokinetic parameter (e.g.,
percent orally bioavailability) based on the information gleaned from the structure evaluation process.
viii
PREFACE (cont’d)
Although the workbook and associated on-line content (available to instructors only) are designed to
allow learners to conduct a self assessment of their knowledge, other audiences are also likely to derive
benefit. Those individuals who teach organic chemistry to pre-health profession students may find the
use of clinically relevant agents in these problems valuable in enhancing student engagement. Pharmacy
faculty tasked with “dusting the rust” off of prerequisite course content may find the workbook a valu-
able alternative to graded homework assignments. For those pharmacy faculty who contribute to an
integrated sequence and have precious little time to review these fundamental concepts, we offer this
workbook (and previous textbook) as a solution to quickly, but thoroughly translate organic chemistry
concepts into chemistry meaningful for the pharmacy practitioner. We hope that you find the format of
the workbook amenable to modification and that you enjoy solving a variety of problems for which drug
structure evaluation can contribute.
We are thankful to have had the opportunity to contribute to learner self assessment and for those
faculty who appreciate the absolute need for practice prior to mastery.
Robin M. Zavod
Marc W. Harrold
ix
ACKNOWLEDGMENTS
The writing and publishing of this text could not have been accomplished without the hard work and
the support of others. We would like to thank the following individuals from ASHP who provided us with
this opportunity and who were extremely valuable in answering our many queries: Ruth Bloom, Robin
Coleman, and Johnna Hershey. Your thoughtful edits and suggestions were exceptionally helpful.
Over my lifetime several individuals have asked me if I think that fast or accurate is more important. My
response has always been, “Who cares about fast, if it isn’t accurate?” A slow, methodical approach to
problem solving has always served me well. Working through practice problems is one method to cement
problem solving skills. I would like to acknowledge both my eighth grade chemistry teacher GH and my
parents for instilling the value of “accurate.” I would also like to thank Marc for putting up with all of
my varied challenges through this self-assessment book and our former textbook projects.—RZ
I am thankful for the opportunity to enhance our initial text and to expand its potential use. I would like
to thank Robin for her original idea for this self-assessment text; my colleagues at Duquesne University
who have provided valuable suggestions; my wife Barbara and my family for their love and support; and
God for His many blessings.—MH
Part 1 QUESTIONS
Section 1 - General Self Assessment

1.1 Functional Group Characteristics and Roles.................... 3
1.2 Identifying Acidic and Basic Functional Groups............... 7
1.3 Solving pH/pKa Problems............................................... 11
1.4 Salts and Solubility........................................................ 13
1.5 Drug Binding Interactions.............................................. 17
1.6 Stereochemistry and Drug Action.................................. 21
1.7 Drug Metabolism........................................................... 23
Structures for 1.1 and 2.1 1.1 Functional Group Characteristics

The bold has been removed. and
The exact same structures are in both of these chapters, but I have Roles
provided two
copies in the event you wanted that.
1. Shown below are the structures of warfarin, phenytoin, bromfenac, and salmeterol.
a. Identify each of the boxed functional groups.
A
F
D
Warfarin G
B Bromfenac
Phenytoin
H
J K
I L
Salmeterol
Box Functional Group Name

A
B
C
B D
D A
O C O C H3
E
H 2N S N
F OH H O
N
G O
H Ibuprofen Sulfamethoxazole
I
J
K
L
3
4 Medicinal Chemistry Self Assessment
Structures for 1.1 and 2.1
The bold has been removed. The exact same structures are in both of these chapters, but I have provided two
b. For each of the functional groups you identified, indicate if it is hydrophilic or hydrophobic in
character.
copies in the Also
event you provide
wanted a brief explanation for your response.
that.
Box Hydrophilic or Hydrophobic
A
B
A
C F
D C
E
E
F
G D
Warfarin G
H B Bromfenac
Phenytoin
I
J
K
H
L
J K
I L
Salmeterol
2. Shown below are the structures of ibuprofen and sulfamethoxazole. Four functional groups have
been highlighted. Based on their electronic properties AND their relative positions in the molecule,
identify if they are electron withdrawing or electron donating. Additionally, identify if this effect is
due to resonance or induction.
B D
A O C H3
O C
H 2N S N
OH H O
N
O
Ibuprofen Sulfamethoxazole
Page1of2

overall evaluation of how each change will affect the chemical properties of imipramine.
1.1 Functional Group Characteristics and Roles 5
N
3. Shown below is the structure of imipramine as well as three analogs. Evaluate each analog and
provide an overall evaluation of how each change will affect the chemical properties of imipramine.
C H3
Imipramine N
C H3
Imipramine
N N N
Cl CH3
O
C H3 C H3
N N N C H3
Analog A C H3 Analog B C H3 Analog C C H3
Analog A Analog B Analog C
4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side chains of the
four amino acids have been boxed.

4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side
chains of the four amino acids have been boxed.
O N H2
O
O OH O
H
N N R2
R1 N H N
H H
O O
HO
a. Identify the four amino acids that comprise this tetrapeptide sequence.
b. For each amino acid, identify the key chemical properties of its highlighted side chain.
Answers can be found in Section 2.1 [this will be linked to section 2.1 title] Page2of2

Note: The questions in this chapter are related to Chapter 2 in Harrold MW and Zavod RM, Basic Concepts in
Medicinal Chemistry, American Society of Health-System Pharmacists, ©2013.
1.2 Identifying Acidic and Basic

Functional Groups
1.2
1. For each of the drugs or experimental drugs shown below, identify all of the acidic and basic functional
groups.
groups.
Experimental oral anticoagulant Bromfenac
Sorbinil
Experimental antidiabetic agent
5. Shown below is the structure of clonidine, an D adrenergic agonist that can be used to treat hypertension.
Drug Name Acidic Functional Groups Basic Functional Groups
Clonidine contains a guanidine functional group (highlighted in bold) that has a pKa of 8.3. Other guanidine
Experimental Oral Anticoagulant
functional
Bromfenac groups, such as that seen with arginine are much more basic with a pKa of 12.5. Provide a chemical
Sorbinil
explanation for this difference.
Experimental Antidiabetic Agent
pKa = 12.5
pKa = 8.3
Clonidine Arginine
7
1.2
groups.
2. Using any one of the acidic functional groups that you identified in question 1, provide an explana-
tion as to why the functional group is acidic. Also provide a similar type of analysis for any one of the
basic functional groups that you identified in question 1.
3. Using the structures from question 1, modify all of the acidic functional groups to show their ionized
forms and in the table below identify the normal pKa range for the specific functional group.
Drug Name Experimental oral anticoagulant

Acidic Functional Group NormalBromfenac
pKa Range
Bromfenac
Sorbinil
4. Using the structures from question 1, modify all basic functional groups to show their ionized forms
and in the table below identify the normal pKa range for the specific functional group.
Sorbinil
Drug Name Basic Functional Group Experimental

Normal antidiabetic agent
pKa Range
Bromfenac
Sorbinil below is the structure of clonidine, an D adrenergic agonist that can be used to treat hypertension.
5. Shown
functional groups, such as that seen with arginine are much more basic with a pKa of 12.5. Provide a chemical
5. Shown below is the structure of clonidine, an α2 adrenergic agonist that can be used to treat hyper-
tension. Clonidine contains a guanidine functional group (highlighted in bold) that has a pKa=8.3.
explanation for this difference.
Other guanidine functional groups, such as that seen with arginine, are much more basic with a
pKa=12.5. Provide a chemical explanation for this difference.
pKa = 12.5
pKa = 8.3
Clonidine Arginine
Page1of2

1.2 Identifying Acidic and Basic Functional Groups 9
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug molecule,
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug
an amphoteric
molecule, drug a nonelectrolyte.
molecule, or drug
an amphoteric molecule, or a nonelectrolyte.
O NH O COOH
CF3
N
H H 2N N N
H
O NH
N S C H3
O H
N
N O
Lomitapide H
CF3
C H3
Argatroban
HO OCH3
COOH
OH
O
H O NH
H3C O Cl N S
H N N H2
C H3 C H3 H O C H3
H 2N N N H2 N
O O
HO Amiloride
CH2 N(CH3 )2
Pravastatin
Diltiazem
Drug Molecule Acid/Base Character of Drug Molecule
Lomitapide
Argatroban
Pravastatin
Amiloride
Diltiazem
Answers can be found in Section 2.2 [this will be linked to section 2.2 title]
Page2of2
1.3 Solving pH/pKa Problems
1. Shown below are the structures of cefotaxime, nitrofurantoin, atenolol, and ezetimibe. Each of these drug
moleculescontains
molecules contains one
one ionizable
ionizable functional
functional group.
group. The
The pK pKa values
a values havehave
beenbeen provided.
provided.
a. Match the pKa values provided with the appropriate functional groups. For each functional group,
b. For the
identify each functional
name of thegroup
groupindicate acidicbeorprimarily
whetherititiswould
and whether basic. ionized or primarily unionized at a
b. Forfor cefotaxime
each at agroup
functional plasma pH of 7.4,
indicate nitrofurantoin
whether it wouldatbe
a urinary pH ionized
primarily of 6.1, aor
stomach pH unionized
primarily of 1.8. at a
stomach pH=1.8, a urinary pH=6.1, or a plasma pH=7.4. Provide an explanation for your responses for

cefotaxime at a plasma pH=7.4, nitrofurantoin at a urinary pH=6.1, and atenolol at a stomach pH=1.8.
Cefotaxime Nitrofurantoin
Nitrofurantion
pKa = 3.4 pKa = 7.1
Atenolol
pKa = 9.6 Ezetimibe
pKa = 10.2
Drug (pKa Value) Stomach (pH=1.8) Urine (pH=6.1) Plasma (pH=7.4)

3. Shown
Cefotaxime below is the structure of natamycin. It contains two functional groups that could be potentially ionized.
(3.4)
Nitrofurantoin (7.1)
The pKa values for natamycin are 4.6 and 8.4.
Atenolol (9.6)
Ezetimibe (10.2)
O OH
O OH
H3C O OH O
COOH
11
O O C H3
Atenolol
pKa = 9.6 Ezetimibe
pKa = 10.2
2. In the previous question, we examined four pKa values in three different environments for a total
of 12 different scenarios. Which of these 12 scenarios allow you to use the Rule of Nines to calculate
the percent of ionization of the functional group in the specific environment? Identify the specific
scenarios and use the Rule of Nines to calculate the percent of the functional group that would be
ionized.
3. Shown below is the structure of natamycin. It contains two functional groups that could be potentially ionized.

3. Shown below is the structure of natamycin. It contains two functional groups that could be poten-
tially ionized. The pKa values for natamycin are 4.6 and 8.4.
O OH
O OH
H3C O OH O
COOH
O O C H3
Natamycin
HO OH
N H2
a. Match the pKa values provided to the appropriate functional groups and identify if the functional
group is acidic or basic.
b. Using the Henderson-Hasselbalch equation, calculate the percent ionization that occurs for each
of these functional groups at an intestinal pH=6.2.
4. The most basic functional group present within the structure of ranitidine has a pKa value of 8.2. Identify this
Page1of2
functional group and calculate the pH that is necessary for this functional group to be 70% ionized.
4. The most basic functional group present within the structure of ranitidine has a pKa=8.2. Identify this
Ranitidine
1.4 Salts and Solubility
1.4 molecules
1. Some drug Author Query
can beResponse
formulated as either a potassium salt or hydrochloride salt. Evaluate all of
the acidic and basic functional groups in each of the drug molecules drawn below and fill in the grid with
the appropriate information.
OH H
N H 2N
O
CH 3
HO OCH3 OH
N H
H Cl
O Arformoterol Baclofen
O
N F CO2 H
H 3C
N O N N
H N N N
N
HN
Irbesartan
Ciprofloxacin
H 3C CH 3
HO CH 3 N
H
OH
NH 2
OH
OH O OH O O
Tetracycline

13

Name of Functional Is the Potassium Name of Functional Is the Hydrochloride

Name of Drug Group That Can Form Salt Acidic, Basic, or Group That Can Form a Salt Acidic, Basic, or
Molecule a Potassium Salt Neutral? Hydrochloride Salt Neutral?
2. Each of these drug molecules will treat a particular ailment by either managing a symptom or
modulating a biochemical pathway. In either case, the drug has to get to its biological target. Using your
knowledge about functional group character, describe how both of the drugs get to their respective
2. Eachtargets.
biological of theseConsider
drug molecules will treat
the concepts a particular
of solubility, ailment
absorption, by either managing
distribution, a symptom
and route of or modu-
administration
lating a biochemical pathway. In either case, the drug has to get to its biological target. Using your
knowledge
in your answer. [pHabout functional
(stomach) group
= 1; pH character,
(intestine) = 8; pHdescribe how
(plasma) = both
7.4] of the drugs get to their respective
biological targets. Consider the concepts of solubility, absorption, distribution, and route of adminis-
tration in your answer. [pH (stomach) = 1; pH (intestine) = 8; pH (plasma) = 7.4]
Cl NCH3
OH
O
O
N CH2OH
O
CONH2
Scopolamine
Loperamide
Biological Targets and Routes of Administration

3. Based on your µstructural
Loperamide: evaluation,
opioid receptors provide
located a rationale
in the for whyoral
large intestine; each of these drugs cannot be
administration
delivered via an oralmuscarinic
Scopolamine: route of administration, or why there
acetylcholine receptors (M1)islocated
limited in
absorption of thenervous
the peripheral drug when it is
systems;
transdermal administration
administered orally.
3. Based on your structural evaluation, provide a rationale for why each of these drugs cannot be deliv-
ered via an oral route of administration, or why there is limited absorption of the drug when it is
Insulin Structure PO3Na2
S S H2N PO3Na2 A Chain

O H Asn Tyr Cys Asn COOH
H2N Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu
S S
S Alendronate S B chain
H2 N Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg
Insulin
Gly
HOOC Thr30 Lys29 Pro28 Thr27 Tyr Phe Phe

nistered orally.
1.4 Salts and Solubility 15
PO3Na2
H2N PO3Na2
OH
Alendronate
Insulin
4. Based on your structural evaluation of embeconazole, answer the following questions:
Embeconazole
Can it be formulated as:
a. a topical ointment or cream? YES NO

b. an aqueous solution? YES NO
c. Which structural features and corresponding characteristics did you consider when answering
each of these questions?
1.5 Drug Binding Interactions
1. Both delapril and lisinopril are inhibitors of angiotensin converting enzyme (biological target) and as such
are valuable drugs used in the management of hypertension. The active form of these drugs requires the
presence of two carboxylic acids or two functional groups that can participate in similar types of interactions
at physiological pH. One of the carboxylic acids interacts with an active site arginine residue, and the other
interacts with a Zn+2 atom. Both of these interactions are critical for drug action. Do the following:
a. Modify the molecules below to show the form of the active drug at physiological pH (pH=7.4).
b. Identify the type1.5
ofAnswer
interaction possible
to Author between the carboxylic acids and the residues present within
Queries
the biological target.

Zn+2
Delapril
Delapril

Zn+2
Lisinopril
Lisinopril
17
2. Tolterodine (Detrol®), fesoterodine (Toviaz®), and oxybutynin (Ditropan®) are anticholinergic agents
used
usedinin
thethe
treatment of overactive
treatment bladder.
of overactive Based
bladder. on the
Based onstructure evaluation
the structure process
evaluation described
process in
described in
Chapter 6* and previous chapters,* “read” each of these drug molecules and determine how each
of these drug molecules interact via hydrogen bonding with the muscarinic receptor. Fill in the grid
provided with your answers.
Tolterodine Fesoterodine
Oxybutynin
Function
Function One amino acid that interacts (via side
H-bond donor, chain) with the functional group via a
Name of Name of ALL Anticholinergics H-bond acceptor, complementary H-bonding interaction;
Functional Group That Contain Functional Group both or neither NONE is a possible answer
1.5 Drug Binding Interactions 19
3. Each
3. Each of the
of the three
three odorant
odorant molecules
molecules drawn
drawn below
below produces
produces a unique
a unique scent
scent on on interaction
interaction with
with the
the
olfactory receptors. Unlike most biological targets for drug action, olfactory receptors typically have
olfactory
an affinityreceptors. Unlike
for a wide most
variety biologicalmolecules
of odorant targets forand
drug
canaction,
adoptolfactory receptors typically
unique conformations have an
to enhance
the affinity of a given odorant for the receptor. Based on the structural features found in each mole-
physiological pH? Indicate which functional group(s) can participate in each of the interactions identified.
cule, what type of interactions are possible with the olfactory receptors at physiological pH? Indicate
which functional group(s) can participate in each of the interactions identified.
Sclareol Nerolidol
(herbal scent) Vanillin (green
(greenwoody
woody scent)
scent)
Sclareol Vanillin Nerolidol

Interaction Type Functional Group Interaction Type Functional Group Interaction Type Functional Group
van der
4. Waals,
There are five basic flavors van
thatderour
Waals, van der
taste receptors detect: salty, Waals,sweet, bitter, and umami
sour,
Hydrophobic Hydrophobic Hydrophobic
(savory).
Hydrogen bond The taste receptors areHydrogen
locatedbond
on taste buds that are on our tongue,
Hydrogen soft palate, epiglottis, and
bond
(acceptor and donor) (acceptor) (acceptor and donor)
Ion–dipole Hydrogen bond
(as the dipole) (donor)
CO2 HIon–dipole
(as the dipole)
H 2N CO2 H
Glutamic Acid Cucumber flavor Green Pepper Flavor

O
N H
N
O
HO P N N
HO O O
OH
HO
Shitaki Mushrooms
Inosinic Acid
Sclareol Nerolidol
20 (herbal scent)
Medicinal
Chemistry Vanillin
Self Assessment (green woody scent)
4. There are five basic flavors that our taste receptors detect: salty, sour, sweet, bitter, and umami
(savory). The taste receptors are located on taste buds that are on our tongue, soft palate, epiglottis,
and are
4. There upper
fiveesophagus. Sour
basic flavors andour
that salty flavors
taste are mediated
receptors by ionsour,
detect: salty, channels,
sweet,whereas sweet,
bitter, and bitter,
umami
and umami flavors are derived from activation of the respective G-protein coupled receptor. The
(savory). The receptor
umami taste receptors are located
is activated on taste
by L-amino budsspecifically
acids, that are onglutamate.
our tongue,Determine
soft palate,which
epiglottis, and
interactions
are possible with the side chain of glutamate (at physiological pH) and then determine if any of the
following flavor molecules can interact with and activate this receptor.
CO2 H
H 2N CO2 H

O
N H
N
O
HO P N N
HO O O
OH
HO
Shitaki Mushrooms
Inosinic Acid
Note: References to chapters are to Chapter 6 in Harrold MW and Zavod RM, Basic Concepts in Medicinal
Chemistry, American Society of Health-System Pharmacists, ©2013.
1.6
1.6 Stereochemistry and Drug Action
Stereochemistry and Drug Action
1. Shown below are the structures of acebutolol, estradiol, cefamandole, and nifedipine. For each of these
compounds, identify all chiral centers.

compounds, identify all chiral centers.
N OH
O O
OH
HN HO
Estradiol
O
Acebutolol
H
H3C N C H3
O
S H3 CO2 C CO2 CH3
N C H3
H NO2
OH N S N
O N
CO2 H N N
Cefamandole Nifedipine
2. For each of the four drug molecules shown in question 1:

a. Identify if it can have an enantiomer. Provide an explanation for your response.
b. Identify if it can have a diastereomer. Provide an explanation for your response.
c. Identify if it can have a geometric isomer. Provide an explanation for your response.
21
3. Shown below is the structure of fluvastatin, an HMG-CoA reductase inhibitor used to lower plasma LDL levels.
Fluvastatin contains two chiral centers, designated as A and B. Using the structure of fluvastatin and the Cahn-
Medicinal Chemistry Self-Assessment Book: Batch Two
3. Shown below is the structure of fluvastatin, an HMG-CoA reductase inhibitor used to lower plasma
Chapters 1.6 and 2.6
Ingold-Prelog (CIP)
LDL levels. system, determine
Fluvastatin contains the
twoR/S configurations
chiral for each ofasits1 chiral
centers, designated and 2.centers.
Using the structure of
fluvastatin and the Cahn-Ingold-Prelog (CIP)
Revised system,
structure determine
reflects the R/S#1configurations
chiral carbons and #2. for each of its
chiral centers.
H O A1
CO2 H
2
B OH
H
C H3
F
N
C H3
Fluvastatin
Fluvastatin
4. Shown below is the enantiomer of fluvastatin. Which of the following properties/actions would
be expected to be identical for fluvastatin and its enantiomer and which would be expected to be
4. Shown below is the enantiomer of fluvastatin. Which of the following properties/actions would be expected to
different?
a. Hepatic
be identical metabolism
for fluvastatin and its enantiomer and which would be expected to be different?
b. Water solubility
a. Hepatic metabolism
c. Adverse effect profile
d. b. Active
Waterrenal
solubility
reabsorption by transport proteins
e. Potency (dosage given)
f. Percent ionization at a pH=7.4
Enantiomer of
Fluvastatin
Page2of2

1.7
Drug Metabolism 1.7 Drug Metabolism

1.7
1. Heroin is a synthetic derivative of the naturally occurring opioid analgesic morphine. Given its illicit into
Drug Metabolism
morphine.
1. Heroin Which phase
is a synthetic I transformation
derivative is responsible
of the naturally for the
occurring conversion
opioid of heroin
analgesic to morphine?
morphine. Given its illicit nature,
heroin is not subject to Food and Drug Administration (FDA) regulation; therefore, the actual composition
of1.aHeroin
given heroin batch derivative
is a synthetic varies significantly. The three
of the naturally molecules
occurring opioid drawn below
analgesic represent
morphine. theitsthree
Given illicit major
into
components found within a batch of heroin. The users’ intense rush has been attributed to the conver-
morphine.
sion Which
of heroin intophase I transformation
morphine. Which phase is responsible for the conversion
I transformation of heroin
is responsible for thetoconversion
morphine? of heroin to
morphine?
Heroin Morphine
Heroin Morphine
2. Estradiol, the estrogen component of many oral contraceptives, undergoes a phase II conjugation
reabsorbed (at least in part). Consider the structure of estradiol drawn below and do the following:
2. Estradiol, the estrogen component of many oral contraceptives, undergoes a phase II conjugation reac-
tion to produce a metabolite that is eliminated via a fecal route (at least in part). The conjugated hormone
a. Modify the structure drawn below to show the product of a sulfate conjugation (phase II
2. Estradiol,
undergoes the estrogen
a process component of many
called enterohepatic oral In
recycling. contraceptives, undergoes
this process the a phase is
sulfate conjugate II cleaved
conjugation
by gut
bacteria to regenerate the active
transformation). drug, which is then reabsorbed (at least in part). Consider the structure of
reabsorbed
estradiol drawn(at least
belowin and
part).do
Consider the structure of estradiol drawn below and do the following:
the following:
a. Modifyb. the
Which enzymedrawn
structure is required
below toto
make
showthis sulfate
the conjugate?
product of aofsulfate conjugation
a. Modify the structure drawn below to show the product a sulfate conjugation(phase
(phaseIIII
transformation).
c. Which deconjugating enzyme catalyzes removal of the sulfate group thus allowing for
b. Which enzyme transformation).
is required to make this sulfate conjugate?
c. Which enterohepatic recycling?
b.deconjugating
Which enzyme enzyme catalyzes
is required to makeremoval of the
this sulfate sulfate group thus allowing for
conjugate?
enterohepatic recycling?
Estradiol
Estradiol
23
3. Metabolites do not necessarily have the same mechanism of action as the parent drug. In the case of
chlorimipramine (a tricyclic antidepressant that inhibits serotonin uptake), a phase I transformation
produces a metabolite that is also a tricyclic antidepressant, but whose mechanism of action is via
3. Metabolites do not of action as the parent drug. In the case of I transformations are possible?
inhibition of norepinephrine reuptake. Which phase I transformation has occurred? What additional
3. Metabolites
phase do not of action
I transformations as the parent drug. In the case of I transformations are possible?
are possible?
Chlorimipramine
Chlorimipramine

4. Evaluate each of
4. Evaluate theoffollowing
each the phase Imetabolic transformations
metabolic transformation and determine which phase I metabolic
has occurred.
transformation has occurred.
4. Evaluate each of the phase I metabolic transformation has occurred.
H
N C H3 N H2
H
CN
H3 C H3 C H 3N H
2
CF3 C H3 CF3 C H3
CF3 Dexfenfluramine CF3
Dexfenfluramine
Fluvoxamine

Fluvoxamine
Baclofen
Baclofen
Part 1 QUESTIONS
Section 2 – Whole Molecule Drug

Evaluation
1.8 Aliskiren....................................................................... 27
1.9 Aripiprazole.................................................................. 31
1.10 Cefprozil....................................................................... 35
1.11 Cetirizine...................................................................... 39
1.12 Chlorpropamide and Other Sulfonylureas.................... 41
1.13 Dabigatran Etexilate.................................................... 43
1.14 Fenofibrate and Gemfibrozil......................................... 47
1.15 Fluvoxamine................................................................. 51
1.16 Haloperidol.................................................................. 55
1.17 Hydrocortisone............................................................. 57
1.18 Levothyroxine (T4)........................................................ 61
1.19 Lidocaine...................................................................... 65
1.20 Montelukast and Zafirlukast........................................ 69
1.21 Phenobarbital and Other Barbiturates......................... 71

1.22 Pravastatin and Fluvastatin.......................................... 73
1.23 Quinapril...................................................................... 75
1.24 Rivastigmine................................................................ 79
1.25 Sitagliptin..................................................................... 83
1.26 Sorafenib...................................................................... 87
1.27 Zanamivir and Oseltamivir........................................... 91
1.8 Aliskiren
Aliskiren is an orally active agent used in the treatment of hypertension. This non-peptide drug acts as an inhibitor
of renin, the enzyme that converts angiotensinogen (its endogenous substrate) to angiotensin I. Biologically inactive,
angiotensin I is rapidly converted to angiotensin II by angiotensin converting enzyme. Angiotensin II is a potent
agonist when bound to its receptor and produces significant vasoconstriction, as well as an increase in blood pressure.
In the presence of aliskiren, angiotensinogen is not converted to angiotensin I so less angiotensin II is produced to
activate the angiotensin II receptor. Consequently, less vasoconstriction occurs, and a drop in blood pressure results.
1. Conduct a structural evaluation of aliskiren, focusing on the boxed functional groups, and use the infor-
mation in the grid toChapter
inform 1.8/2.8 (removetobold
your answers the from drug name
questions x2)
that follow.
E
D F
A
B
Aliskiren
C
Function
Character Function Amino Acids That
Acidic, Basic, Interaction(s) Can Interact with the
Character Function Functional Group via
or Neutral Possible with
Name of Hydrophilic Provide ↑ Solubility Biological Target Ion–Dipole Interactions
Functional and/or pKa When and/or at Physiological at pH=7.4
Group Hydrophobic Relevant ↑ Absorption pH=7.4 None Is Acceptable
Aliskiren
A
B
C
D
E
F
27
B
Aliskiren
2. Aliskiren is marketed as the pure 2S, 4S, 5S,C7S enantiomer. Circle all of the chiral carbon atoms and
determine if diastereomeric or geometric isomers are possible.
Aliskiren
3. Although aliskiren is administered orally, its oral bioavailability is ~2.5% and is very poorly absorbed.
Using the information in the structure evaluation grid, provide a structural rationale for this unfortu-
nate property.
4. Approximately 25% of the absorbed dose of aliskiren is excreted in the urine unchanged. It is
unknown how much of an absorbed dose is metabolized, and several metabolites from CYP3A4
mediated transformations have been identified. Several possible metabolic products are illustrated.
Identify which metabolic transformation has occurred and whether or not it represents an oxidative
transformation.
1.8 Aliskiren 29
Missing diagram for Question #4 (Chapter 1.8/2.8)
Name of Metabolic Transformation Oxidative or Non-Oxidative

A
B
C
D
E
2.
30 2.
Medicinal Chemistry Self Assessment
2.
Aliskiren
5. Renin catalyzes the cleavage of a specific Leu-Val peptide bond within the structure of angiotensin-
2. The structure of aliskiren contains functional groups that mimic the side chains for these two
ogen.
amino acids. The hydrolyzable peptide bond (found between Leu-Val) has been replaced by a non-
5.hydrolyzable
Renin
2. non-hydrolyzable hydroxyethylene
hydroxyethylene group.
group in aliskiren. Circle the functional groups that mimic the amino
acid side chains of these two amino acids and box the non-hydrolyzable hydroxyethylene group.
2.
2.
2.
(remove bold from drug name) Chapter 2.8
2.
2.
2.
2.
2.
6. Aliskiren can be co-administered with other anti-hypertensive agents to provide better hypertension
2.
management. Amlodipine is a second generation dihydropyridine calcium channel blocker used in
Aliskiren
the treatment of hypertension. Aliskiren and amlodipine are both plasma protein bound (47–51%
and2.93–97%, respectively). How likely is it that a plasma protein binding interaction will occur if
these drugs are co-administered?
2. (remove bold from drug name) Chapter 1.8/2.8
Amlodipine
1.9 Aripiprazole
1.9 Aripiprazole
Shown below is the structure of aripiprazole, a serotonin receptor modulator used for the treatment of depression,
schizophrenia,
Shown autism,
below is the mania,
structure and bipolar disorder.
of aripiprazole, a serotonin receptor modulator used for the treatment of depression,
schizophrenia, autism, mania, and bipolar disorder.
O
H
N
Cl Cl O
N N
Aripiprazole
1. Identify
1. all of theallacidic
Identify of theand
pH basic
of 5.6.functional groups, provide the normal pKa range for each of the identi-
fied functional groups, and identify if each functional group would be primarily ionized or unionized at a
urine 2. solubility of aripiprazole.
pH=5.6.
3. Using yur answers previously listed.
4. all
2. Identify Drug hly aripiprazole
of the and either groups,
remaining functional tolbutamide
andor losartan?
indicate how each group contributes to the overall
water solubility or the overall lipid solubility of aripiprazole.
3. Using your answers from the previous two questions, provide an explanation as to why aripiprazole can be
administered orally for the indications previously listed.
Tolbutamide
Losartan
5. Assume that at a physiological pH of 7.4.
D
31
A
Aripiprazole
N N

1. Identify all of the pH of 5.6. Aripiprazole
2. solubility of aripiprazole.
4. 1.
Drug molecules
3.Identify
Usingall that
yurofanswers
the pHareofpreviously
highly
5.6. plasma
listed.protein bound may undergo a drug interaction due to the
displacement of one drug molecule from a plasma protein by another drug molecule. Shown below
2.
are4.solubility
Drug
the hlyofaripiprazole
structures aripiprazole.and either
of tolbutamide andtolbutamide or losartan?
losartan. Both of these drugs are highly plasma protein bound.
Aripiprazole is also highly plasma
3. Using yur answers previously listed. protein bound (greater than 99%). Would you expect there to be a
drug interaction between aripiprazole and either tolbutamide or losartan?
4. Drug hly aripiprazole and either tolbutamide or losartan?
Tolbutamide
Tolbutamide Losartan
Losartan
5. Assume that the boxed functional groups
5. Assume that at a physiological pH of 7.4.of aripiprazole form four key binding interactions with
a serotonin receptor. Further assume that these binding interactions occur with the side chains of
Tyr, Asp, Ile, and Gln. Using this information, identify four possible binding interactions between
aripiprazole
5. andatthe
Assume that given aminopH
a physiological acids. Assume that this binding interaction occurs at a physiological
of 7.4.
pH=7.4. D
A
C D
A B
C
B
Aripiprazole
Aripiprazole
1.9 Aripiprazole 33
6. Shown below are three known metabolites of aripiprazole. Identify the metabolic transformations that
6. Shown below are three known metabolites of aripiprazole. Identify the metabolic transformations
would be required to form each of the metabolites. For each metabolic transformation, indicate if it is
that would be required to form each of the metabolites. For each metabolic transformation, indicate
aifphase I transformation
it is a phase or a phase
I transformation or aII phase
transformation.
II transformation.
O
H
N
Cl Cl O
HO N N
Metabolite A
O
H
N
Cl Cl O
OH
N N
Metabolite B
O
H
N
Cl Cl O
OH
N NH HO
O
Metabolite C
1.10 Cefprozil
Cefprozil is a second-generation cephalosporin that exhibits good Gram (+) activity with improved Gram (–) activity
as compared to the first-generation cephalosporins. Effective against the majority of bacteria that cause upper and
lower respiratory infections, as well as skin infections, cefprozil was a first-line anti-infective agent until an increase in
the incidence of resistance and the development
Chapter of (remove
1.10/2.10 newer agents decreased
bold from its “favored” status.
drug name)
Cefprozil (Cefzil)
1. Conduct a complete structural evaluation

Chpater ofCorrected
1.10/2.10 cefprozil structure
and use the information
(product in the grid to inform your
of E transformation)
answers to the questions that follow.
NH 2 H
H H
HO Function N S Function
Character Amino Acids That
Interaction(s)
Character Acidic, Basic, Function O N Can Interact with
HO Possible with
O CH 3
O
or Neutral H Functional Group via
Name of Hydrophilic H↑ Solubility
H Biological Target CO2H
Functional and/or Provide pKa N and/orS at Physiological H-Bonding (at pH=7.4)
N H2
Group Hydrophobic When Relevant
O
↑ Absorption
N
pH=7.4 None is Acceptable
OH
HO O C H3
H H
CO2 H O H 2N S
HO
N
A B O
CO2 H
C
N H2 H
H H
N S
O N
HO O C H3
CO2H
NH 2 H D
H H
F
N S
E
O N
HO O CH 3
N H2 H
H H
O 35 N H N S
O
O
S O N
-O O
2. Based on the information in the structure evaluation grid, determine if cefprozil is an acidic, basic, or
amphoteric drug. Provide a brief explanation for your answer.
3. Cefprozil is administered orally as a tablet or liquid suspension. Consider each of the acidic and basic
functional groups and determine whether each group will be predominantly ionized or unionized
as it moves through the gastrointestinal (GI) tract, into systemic circulation, and then into the urine.
[The relevant pKa values=10, 1.7, and 7.2.] Complete the grid below.
Ionized or Ionized or Ionized or

Name of Acidic or Ionized or Unionized Unionized Unionized at Ionized or
Functional Basic Unionized at at pH=1 at pH=7.4 pH=8 Unionized at
Group (pKa) pH=5 (saliva) (stomach) (plasma) (intestine) pH=6 (urine)
4. Given the predominant ionization state of these acidic and basic functional groups as they
traverse the GI tract and the information in the structure evaluation grid, determine in which GI
compartment(s) drug absorption could occur.
1.10 Cefprozil 37
5. Approximately 60% of a cefprozil dose is recovered in the urine unchanged. Because impairment in
Cefprozil
hepatic function (Cefzil) the half-life of the drug by several hours, it is likely that cefprozil under-
increases
goes a variety of metabolic transformations catalyzed by liver enzymes. For each of the metabolic
transformations A–F, identify which metabolic transformation has occurred and whether the product
Chpater
formed1.10/2.10 Corrected
was the result of a structure (product
phase I or phase of E transformation)
II metabolic transformation.
NH 2 H
H H
HO N S
O N
HO O CH 3
O H
H H CO2 H
N S
N H2
O N OH
HO O C H3
H H
CO2 H O H 2N S
HO
N
B O CH 3
A
CO2 H
C
N H2 H
H H
N S
O N
HO O C H3
CO2H
NH 2 H D
H H
F
N S
E
O N
HO O CH 3
N H2 H
H H
O N H N S
O
O
S O N
-O O O C H3
OH O
CO2 H
NH 2 H
H H
N S
O N OH
HO O
CO2 H
Name of Transformation Phase I or Phase II

A
B
C
D
E
F
6. Like the penicillins, the cephalosporins suffer from chemical instability of the β-lactam bond. Chem-
ical hydrolysis of this bond renders the drugs in the class of anti-infective agents inactive. This bond
is also subject to cleavage by β-lactamases (due to the presence of a nucleophilic serine side chain
[CH2OH] within the active site of the enzyme). Show how the β-lactam bond can be hydrolyzed by
chemical and enzymatic (β-lactamase) mechanisms.
1.11 Cetirizine
Cetirizine is a popular second-generation antihistamine used in the management of allergy symptoms. It is the
metabolic byproduct produced Medicinal
from the prescription
Chemistryantihistamine hydroxyzine.
Self-Assessment Although
Book: Batch Twocetirizine is labeled non-
sedating and is one of the preferred allergy medications for long-haul
Chapters 1.11 and drivers,
2.11 hydroxyzine causes significant drowsi-
ness that limits its utility in the management of typical allergy symptoms. Hydroxyzine is commonly used in the
treatment of pruritus (severe itching).
Chapter 1.11 (remove bolded drug names)
Cetirizine
Hydroxyzine
1. Conduct a complete structural evaluation of hydroxyzine and use the information in the grid to inform
your answers to the questions that follow.
Function
Function Amino Acids That
A C D
Character E
Can Interact with
Interaction(s)
Character Acidic, Basic, or Function Possible with Functional Group
Name of Hydrophilic Neutral ↑ Solubility Biological Target via H-Bonding (at
Functional and/or Provide pKa and/or at Physiological pH=7.4)
Group Hydrophobic When Relevant ↑ Absorption pH=7.4 None Is Acceptable
B Hydroxyzine
39
2. Name the phase I metabolic transformation(s) that hydroxyzine undergoes to produce cetirizine.
3. Based on your structural evaluation of both hydroxyzine and cetirizine, name ALL of the phase I
metabolic transformations possible.
4. A metabolic product from a phase II metabolic transformation has been identified. Which phase II
transformations can cetirizine undergo?
5. Review the structure of cetirizine (pKa=2.9 and 8.3) and identify all of the acidic and basic functional
groups present. Determine the predominant ionization state of each functional group as it travels
through several compartments of the body after oral administration. Complete the table below.

6. Provide a structural rationale for why hydroxyzine is classified as a sedating antihistamine and cetiri-
zine is categorized as a non-sedating antihistamine.
1.12 Chlorpropamide and

Other Sulfonylureas
1.12 Chlorpropamideand Other Sulfonylureas

Shown below are the structures of tolbutamide and chlorpropamide. These drug molecules are used in the treat-
ment of type 2 diabetes mellitus. They stimulate the release of insulin from the pancreatic β-cells by interacting with
Shown below are the structures of tolbutamide and chlorpropamid of ATP)-sensitive potassium channels.
adenosine triphosphate (ATP)-sensitive potassium channels.
Shown below are the structures of tolbutamide and chlorpropamid of ATP)-sensitive potassium channels.
Tolbutamide Chlorpropamide
1. It is not uncommon for patients with type 2 diabetes to be dually diag and require additional occur?
1. It is not uncommon for patients with type 2 diabetes to be dually diagnosed with hypertension and
require additional pharmacotherapy. In this scenario, it is possible for drug interactions to occur if the
prescribed combination therapy is not appropriately evaluated. Angiotensin II receptor antagonists,
commonly known as angiotensin II receptor blockers (ARBs), are often used to treat hypertension.
Losartan (shown below) is an ARB, and similar to tolbutamide and chlorpropamide, is highly plasma
1.protein
It is not uncommon
bound. for patients
If losartan with type
was selected for2use
diabetes to be dually
in a patient who diag and require
is already takingadditional occur?
tolbutamide or chlor-
propamide, would you anticipate that a drug interaction could occur?
Losartan
Losartan
2. The normal pKa range for sulfonylureas is 5 to 6. When comparing the pKa values of chlorpropamide.
3. Using your answer from percent of tolbutamide that will be ionized at an intestinal pH of 6.1.
2. The
4. normal pKa rangeofforaction
The mechanism sulfonylureas is 5 to 6.groups.
of ion functional When comparing the pKa values of chlorpropamide.
3. Using your answerhas

5. Tolbutamide from percent has
a half-life of tolbutamide thatlonger
a significantly will behalf-life
ionizedthan
at antolbutamide.
intestinal pH of 6.1.
4. The
6. mechanism of is
Shown below action of ionpathways
a known functionalthat
groups.
are required to produce this metabolite.
41
5. Tolbutamide has a half-life has a significantly longer half-life than tolbutamide.
Replacementstructurefortheanswertoquestion2inChapter2.9(Aripiprazole)

2. The normal pKa range for sulfonylureas is 5 to 6.
Alkyl (aliphatic) When comparing the pKa values of chlorpropamide
chain
and tolbutamide, it is found that the(Lipid
sulfonylurea
soluble) of one of these drug molecules has a pKa=5.4 and
the other has a pKa=4.9. Evaluate the structures of Ether
theseoxygen
two drug molecules, assign the pKa values to
provide an explanation(Water
the correct molecules, andHalogens soluble)
for the difference in pKa values. Amide
(Lipid soluble) (Water soluble)
3. Using your answer from question 2, calculate the percent of tolbutamide that will be ionized at an
Hydrocarbon portion
intestinal pH=6.1.
of bicyclic ring
(Lipid soluble)
Aromatic (phenyl) ring
4. The(Lipid soluble) of action of this class of drugs involves the ability to interact with the ATP-sensitive
mechanism
potassium channels in the pancreas. Using the structure of tolbutamide, identify the types of binding
interactions that are possible between its functional groups Aripiprazole
and a protein ion channel. Also identify
amino acids present within this ion channel whose side chains could participate in the interactions
identified. Assume a plasma pH=7.4 for all ionizable functional groups.
Alkyl (aliphatic) chain
(Lipid soluble)
5. Tolbutamide has a half-life of 4.5 to 6.5 hours, whereas chlorpropamide has a half-life of 36 hours.
Propose a chemical/structural reason why chlorpropamide has a significantly longer half-life than
tolbutamide.
Replacement structure for question 6 in BOTH Chapters 1.12 and 2.12 (Chlorpropamide and Other
Sulfonylureas)
6. Glyburide is a second generation sulfonylurea that is structurally similar to chlorpropamide and
tolbutamide. Shown below are the structures of glyburide and one of its known metabolites. Identify
the metabolic pathways that are required to produce this metabolite.
Cl O
O O
S N N
H H
N O
H
O
H3C Glyburide
O OH
O O
H3C S N N
H H
N O
H
Metabolite of glyburide
1.13 Dabigatran Etexilate
Thrombin is the enzyme responsible for catalyzing the conversion of fibrinogen to fibrin. The production of fibrin is
important in the formation of sturdy blood clots. As you might expect, inhibition of thrombin prevents the forma-
tion of fibrin. As shown in the diagram below, a catalytic triad of amino acids (Asp, His, Ser) found in the active site
of thrombin is responsible for hydrolyzing a key peptide bond found within fibrinogen. Orientation of fibrinogen in
the active site ofChapters
thrombin1.13/2.13 Concern
relies on the about of
interaction His (revised
a key diagram
tri-peptide + removed
sequence bolded names)
(D-Phe-Pro-Arg) found within the
structure fibrinogen with key amino acids in the enzyme active site.
Chapters
Dabigatran 1.13/2.13
etexilate Concern about
is administered as a His (revised
prodrug. diagram
In its + removed
active form, boldedetexilate
dabigatran names)is an orally active direct
Thrombin
thrombin inhibitor used in the prevention Activeand
of stroke Siteblood clots in patients diagnosed with atrialThrombin
fibrillation.Active Site
Thrombin Active Site Thrombin Active Site

Thrombin catalyzed
amide hydrolysis
Thrombin catalyzed
amide hydrolysis
Fibrinogen (D-Phe-Pro-Arg)
Fibrin
Chapters 1.13/2.13 (removed bold in drug name) Fibrin
Chapters 1.13/2.13 (removed bold in drug name)
Dabigatran etexilate
Dabigatran
Chapters 1.13/2.13 (removed bold andetexilate
centered text)
Chapters 1.13/2.13 (removed bold and centered text)
3 43
Chapters 1.13/2.13 Concern about His (revised diagram + removed bolded names)
Thrombin
1. Conduct a complete structural evaluation of dabigatran Active(prodrug)
etexilate Site and use the information Throm
in the grid to inform your answers to the questions that follow.
Function
Character Thrombin catalyzed
Function amide hydrolysis
Amino Acids That
Acidic, Basic, Can Interact with
Interaction(s)
Character or Neutral Function Functional Group
Possible with
Name of Hydrophilic Provide pKa ↑ Solubility Biological Target via H-Bonding (at
Functional and/or When and/or at Physiological pH=7.4)
Fibrin
2. Dabigatran etexilate is a non-peptidomimetic prodrug. Provide a brief rationale for the value of
converting an active drug into a prodrug.
3. Dabigatran etexilate rapidly undergoes two esterase-catalyzed hydrolytic reactions to the active drug
dabigatran. Show the products from each of the esterase-catalyzed hydrolytic reactions that occur in
the plasma.
4. In its active form dabigatran mimics the D-Phe-Pro-Arg tripeptide sequence, but does not contain a
peptide backbone (non-peptidomimetic). Review the tripeptide sequence drawn below noting that
there are numbers 1–3 that indicate where
Chapters each amino
1.13/2.13 acid is
(removed located
bold in the sequence.
and centered text) Determine the
types of interactions possible with each of the amino acid side chains.
1 2
D-Phe-Pro-Arg Tripeptide Sequence

1.13 Dabigatran Etexilate 45
5. Review the structure of dabigatran and determine which of the boxed groups will likely mimic the
interactions found within the D-Phe-Pro-Arg tripeptide sequence. Given the three-dimensional
nature of both peptides and small molecules, it is important to remember that the functional groups
within dabigatran do not need
Chapters 1.13/2.13 to linebolded
(removed up in text)
the same order. Using the table provided to guide your
Chapters
analysis, place a Yes 1.13/2.13
or No in each box (removed bolded
to indicate text) the functional group could mimic the
whether
amino acid side chain indicated.
A B E
A B E F F
D
D
C
C
Active form of Dabigatran

Chapters 1.13/2.13 (removed bold drug name)

Chapters
6. Dabigatran etexilate 1.13/2.13
is formulated as(removed bold
a mesylate drug
salt. name)a brief rationale for the value of
Provide
administering the salt form of a drug.
Dabigatran etexilate mesylate

1.14 Fenofibrate and Gemfibrozil
Fenofibrate is a member of the fibrate class of anti-hyperlipidemic agents. It is used as adjunctive therapy to diet in the
management of dyslipidemias, including in the treatment of severe hypertriglyceridemia. The specific mechanism(s)
by which fenofibrate decreases triglyceride and total cholesterol levels, as well as increases the levels of high density
lipoproteins (HDL), is unknown. What we do know is that the decrease in very low density lipoproteins (VLDLs)
1.14 and 2.14 (drug name – remove bold)
results from fenofibrate stimulation of lipoprotein lipase.
Fenofibrate Gemfibrozil
1. Conduct a complete structural evaluation

Letter of bold
“C” – add fenofibrate and use the information in the grid to inform
Function
Amino Acids That

Character Function Can Interact with the
Character Acidic, Basic, or Function Functional Group via
Interaction(s)
Name of Hydrophilic Neutral ↑ Solubility Possible with Biological Hydrogen Bonding
Functional and/or Provide pKa and/or Target at Physiological Interactions at pH=7.4
C
2.14 – remove bold from label
B F
A C D
E
Fenofibrate
2.14 – remove bold from

47
label
Fenofibrate
2. Fenofibrate is administered as a prodrug and undergoes hydrolysis to the active drug. Draw the
active drug. Provide a brief rationale for the value of administering fenofibrate as a prodrug.
1. Conduct a complete structural follow:
2. calculated
3. The Fenofibrate
1.14 andlogis of
2.14 administering
P (drug
for fenofibrate
fenofibrate is 5.24,
name – remove as a prodrug.
whereas
bold) the calculated log P for gemfibrozil is 3.9.
Provide a structural rationale for the difference in this pharmacokinetic property.
3. The calculated in this pharmacokinetic property.
Letter Fenofibrate
“C” – addperspective,
bold Gemfibrozil
4. From an elimination 60% of a fenofibrate dose is found in the urine and 25% is found
1.14 and 2.14 (drug name – remove bold)
in the feces. The active form of fenofibrate undergoes both phase I and phase II metabolic trans-
formations. The phase II conjugate is eliminated in the urine. Oxidative metabolism does not occur.
Evaluate
4. Fromeach of the metabolic
an elimination products
perspective, 60%and
of a determine
ve phase I iftransformation
it is the conjugate
(that that
doesisNOT
eliminated
occur). in the
urine (that does occur), the product of a non-oxidative phase I transformation (that does occur), or
the product of an oxidative phase I transformation (that does NOT occur).
O O
HO O
OH
C
H3 C C Fenofibrate
H3 Gemfibrozil
Cl
ALetter “C” – add bold B
B F
A C D
E
CC
Fenofibrate
Name 2.14 – remove bold from label

2.14of Metabolic
– remove Transformation
bold from label Type of Product
A
B
O
BO C H3 F O O
C
Ester
A O D O
OC C H3 Hydrolysis OH
H3C C H3 H3C C H3
Cl Cl
E
Inactive Active
Fenofibrate

1.14 Fenofibrate and Gemfibrozil 49
5. Provide a structural rationale for why oxidative O-dealkylation does not occur.
6. Fenofibrate and gemfibrozil have dramatically different elimination half-lives (20–22 hours and 1.5
1.14 and 2.14 (drughours
namerespectively). Identify the possible metabolic transformations for gemfibrozil and provide a
– remove bold)
justification for the significant difference in this pharmacokinetic parameter.
Letter “C” – add bold
B F
A C D
E
Fenofibrate
O O C H3 O O
Ester
O O
O C H3 Hydrolysis OH
H3C C H3 H3C C H3
Cl Cl
Inactive Active
O O
O
OH
Cl
H3C C H3
1.15 Fluvoxamine
Fenofibric Acid
Fluvoxamine is an inhibitor of the serotonin reuptake transporter (SERT) and prevents the reuptake of serotonin
at the presynaptic membrane in the central nervous system. It is indicated for use in the treatment of depression.
1.15 and 2.15 – remove bold from label
Fluvoxamine is structurally unique relative to the rest of the serotonin selective reuptake inhibitor class of drugs.
A
B
C D
Fluvoxamine
1. Conduct a structural evaluation 1.15 and 2.15 – remove

of fluvoxamine, bold
focusing onfrom label functional groups, and use the
the boxed
information in the grid to inform your answers to the questions that follow.
F3 C
Function
O Function Amino Acids That

Character C H3
Interaction(s) Can Interact with the
Acidic, Basic,
N NH3 – O Functional Group via
PossibleOwith
Character or Neutral OFunction O
Hydrogen Bonding
Biological
Name of Hydrophilic Provide ↑ Solubility Target Interactions at
Functional and/or pKa When and/or at Physiological OH
pH=7.4
Fluvoxamine maleate
A
B
C
D
E
51
52 Fenofibric Acid
1.Medicinal
ConductChemistry Selfevaluation
a structural Assessmentof
2. for your answer.

2. Fluvoxamine is marketed as a single isomer. Is the product sold as a single enantiomer, diastereomer,
or geometric isomer? Provide a brief rationale for your answer.
A
F C B
3
F3 C
1' C D
O 1' 2'
2' C H3 O
C H3
N NH 2 1N
2 O H 2N 2
1 E O
A B
Fluvoxamine
3. Fluvoxamine is formulated
3. Fluvoxamine as a maleate
is formulated salt. saltes
What typetheof salt is a maleate salt, and what type of
1.15 and 2.15as a maleate
– remove bold fromoflabel drug?
properties does it confer to the overall properties of the drug?
F3 C
O
C H3
N NH3 – O
O O
O
OH
Fluvoxamine maleate
Fluvoxamine maleate
4. Fluvoxamine is wellisabsorbed
4. Fluvoxamine and has an oral bioavailability of ~50%. Using the information found in
well tic properties.
the structure evaluation grid, provide a rationale for these pharmacokinetic properties.
5. A number of occurred.
1.15 Fluvoxamine 53
5. A number of fluvoxamine metabolites have been identified, all of which demonstrate little or no
pharmacological activity. Evaluate each of the metabolic products drawn below and identify which
metabolic transformation has occurred.
A B
C D
F
E
Name of Metabolic Transformation

A
B
C
D
E
F
6. Fluvoxamine is a strong inhibitor of CYP1A2, CYP3A4, and CYP2C19. These enzyme isoforms catalyze
a number of the phase I oxidative metabolic transformations. Several of the benzodiazepines (used
in the treatment of anxiety), including the very popular alprazolam, rely heavily on hepatic oxidation
for metabolic inactivation and elimination. Other benzodiazepines, including the equally popular
lorazepam, rely on glucuronide conjugation for metabolic inactivation and elimination. Which
combination of drugs, fluvoxamine + alprazolam or fluvoxamine + lorazepam, is the most likely to
generate an enhanced anxiolytic effect?
1.16 Haloperidol
Shown below is the structure of haloperidol. Six of its functional groups have been identified.
E
D
C
F
B
1. Using1.theUsing
tablethe
below, identify the six boxed functional groups. For each of the functional groups you
identified, indicate if it is hydrophilic or hydrophobic in character. Also provide a brief explanation for
2. Based on or induction.
your response.
3. Using the.4, and 8.5.
Functional Group Name Hydrophilic or Hydrophobic
A
E
B
D
C C
D
A
E
F
F
2. Based on their electronic properties AND theirB relative positions in the molecule, identify if functional
groups4. A,Shown
C, andbelow
E are modification
electron withdrawing orthe
can enhance electron donating.
duration Additionally, identify if this effect is
of haloperidol.
1. Using the
3. Using2.theBased
unmodified structure of haloperidol and the table below, identify all of the acidic and basic
on or induction.
functional groups present in the structure, provide the normal pKa range for each functional group, and
3. ifUsing
identify eachthe.4, and 8.5.
functional group would be primarily ionized or unionized in pH environments=1.7, 5.5,
6.0, 7.4, and 8.5.
5. Using the table below, identify the groups.
C
4. Shown below modification can enhance the duration of haloperidol.
55 B
D
2. Based
3. Using induction.
on or8.5.
the.4, and
E
D
C
A
Acidic or Primarily Ionized or Unionized

Functional Group Basic pKa Range 1.7 5.5 6.0F 7.4 8.5
B
4.
4. Shown1.below
Shown Using
below is the
a structural
modification analog
can of haloperidol.
enhance the duration Evaluate the structural change and propose an
of haloperidol.
explanation as to how this structural modification can enhance the duration of haloperidol.
induction.can enhance the duration of haloperidol.
4. 2. Based
Shown belowon or
modification
5. Using the table below, identify the types of binding interactions that are possible between the
5. Using the table below, identify the groups.
boxed4.functional groups
Shown below and a protein
modification receptor the
can enhance or enzyme.
duration Also identify amino acids present within
of haloperidol.
5. Using
a receptor orthe table below,
enzyme whoseidentify the groups.
side chains could participate in the interactions that you identified.
Assume a plasma pH=7.4 for all ionizable functional groups.C
B C
B
D
A
D
A
6. Shown below is the perform with haloperidol.

Amino Acids Capable of Forming
6. 5.
Shown below
Using is thebelow,
theGroup
table perform with haloperidol.
identify the groups.
Functional Types of Binding Interactions Specific Binding Interaction
A
B C
C
B
D
D
A
6. Shown below is the structure of haloperidol and a list of five metabolic transformations. For each
metabolic transformation, indicate if it is a phase I or a phase II transformation and if haloperidol has
a functional group present that can participate in the transformation. If you answer YES, then draw
the appropriate metabolite; if you answer NO, then provide a brief explanation as to why this meta-
bolic transformation is not possible to perform with haloperidol.
6. Shown below is the perform with haloperidol.
Metabolic Pathways
A. Reduction
B. Sulfate Conjugation
C. Hydrolysis
D. Oxidative N-Dealkylation
E. Benzylic Oxidation
1.17 Hydrocortisone
Hydrocortisone is a glucocorticoid used in the management of inflammation. Derivatives of hydrocortisone are used
in the management of asthma and chronic obstructive pulmonary disease.
1.17 and 2.17

1. Conduct a complete structural evaluation – remove bold and
of hydrocortisone fromuse
label
the information in the grid to inform
C
F
B
A D
Hydrocortisone
Function Function
Question #3 structure needs to be replaced:
Character
Interaction(s) Amino Acids That
Acidic, Basic, Possible with Can Interact with the
Character or Neutral Function Functional Group via
Biological
Name of Hydrophilic Provide ↑ Solubility Target Ion–Dipole Interactions
Functional and/or pKa When and/or 21 at Physiological at pH=7.4
11 17
A
B A
E 1.18 and 2.18 – remove bold from label
F
E
I D O
A C
HO I
OH
N H2
I O
57
B I
2. The glucocorticoids interact with residues within the glucocorticoid receptor (Arg611, Asn564, Thr739,
Gln642, and Gln570) via hydrogen bonding and ion–dipole interactions at physiological pH (7.4). Iden-
tify which functional groups could interact with the side chains of these amino acids.
Can Interact with

Can Interact with Glutamine642 and
Asparagine564 and Threonine739 Glutamine570 via a
Can Interact with Arginine611 via a Hydrogen Bonding Hydrogen Bonding
via an Ion–Dipole Interaction Interaction Interaction
Functional
Group Yes or No Yes or No Yes or No
A 1.17 and 2.17 – remove bold from label
B
C
D E
E
F
C
F
B
3. Several of the functional groups identified in the structure evaluation grid are essential for biological
activity. There are several metabolic transformations Dthat render the glucocorticoids inactive. These
A
transformations include the following:
1. Ring A ketone reduction
Hydrocortisone
2. Ring A double bond reduction
3. C-17 oxidation
4. C-11 oxidation
21
11 17
Based on this information, consider the array of products drawn in the scheme that follows. Iden-
tify each type of reaction or transformation that has occurred and evaluate each of the products to
1.18or
determine if each product is active and 2.18 – remove bold from label
inactive.
E
I D O
A C
HO I
OH
N H2
I O
B I
L-Thyroxine
1.17 Hydrocortisone 59
A
B
F 21
11 17
C
A
Pathway Type of Reaction or Transformation Active or Inactive

A
B
C
D
E
F
4. The synthetic synthetic solubleare

4. The glucocorticoids ester is present.
often formation
esterified at C-21has an effectprodrugs.
to produce on overall Both
drug water solubility.
lipophilic and
water soluble esters can be formed. Evaluate each of the four prodrugs drawn below and determine
whether a lipophilic or water soluble ester is present. Determine how prodrug formation has an
effect on overall drug water solubility.
A B
C D
Type of Ester Formed Effect on Overall Drug Water Solubility

A
B
C
D
a. Provide a structural rationale for why prodrugs (e.g., B and D) are used in the preparation of
aqueous injectable products to be administered intramuscularly (IM) or intravenously (IV).
b. Provide a structural rationale for why prodrugs (e.g., A and C) are used in the preparation of
depot injections.
5. Lipophilic glucocorticoid esters typically do not concentrate in the urine, but rather undergo glomerular
filtration followed by tubular reabsorption. Provide a brief rationale for why lipophilic glucocorticoid
esters do not concentrate in the urine and determine what effect this has on duration of drug action.
6. Which type of prodrug, water soluble ester salts, or lipophilic esters, would you anticipate to have
greater systemic side effects?
C
F
B
A D
Hydrocortisone
1.18 Levothyroxine (T4)
21
11 17
Levothyroxine (T4) is a naturally produced thyroid pro-hormone. In its active form, tri-iodo-L-thyronine (T3) is
responsible for regulating oxygen consumption and calorigenesis (think metabolism, metabolic rate, and thermogen-
A
esis). T4 is biosynthesized and stored in thyroglobulin molecules until it is needed. Once proteolyzed from thyroglob-
ulin and transported to the desired target tissue, T4 undergoes dehalogenation catalyzed by thyroxine dehalogenase to
the active thyroid hormone T3.
1. Conduct a structural evaluation of Tand

1.18 4
, focusing on thebold
2.18 – remove boxed functional
from label groups, and use the information in
the grid to inform your answers to the questions that follow.
E
I D O
A C
HO I
OH
N H2
I O
B I
L-Thyroxine
Function
Amino Acids That

Character Function Can Interact with
Acidic, Basic, Interaction(s) the Functional
Character Function
or Neutral Possible with Group via Hydrogen
Name of Hydrophilic Provide ↑ Solubility Biological Target Bonding Interactions
A
B
C
D
E
61
HO I
OH
N H2
I62 Tri-iodothyronine
O
B I
2. 2.18
1.18 and Hormone
– removereplacement
bold from
L-Thyroxine )therapy in the form of levothyroxine (T4) is available for those patients who
(T4label
<DAVID_-change caption to Levothyroxine>
do not produce an adequate endogenous supply of T4. Evaluate the structure of levothyroxine and
determine if it is an enantiomer, diastereomer, or geometric isomer.
O
2. Hormone replacement therapy in the geometric I isomer. O
H 2N
OH HO I
H I O OH
H NH
HO I 2
I O OH
OH H I NH
2
I O
L-Tyrosine Levothyroxine
I
Levothyroxine
3. Evaluate the chiral carbon atom in levothyroxine to determine if this drug is drawn as the R- or
S-enantiomer.
3. Evaluate the chiral to determine if this drug is drawn as the R- or S-enantiomer.

4. T3 is the biologically active hormone. It interacts with the thyroid hormone receptor via hydrogen
bonding,
4. T3 is the ion–dipole,
in the structure hydrophobic,
evaluation grid. and ionic interactions. Evaluate the ribbon diagram that shows
how T3 interacts with the surface of the thyroid receptor and identify the types of interactions
possible for each of the five functional groups identified in the structure evaluation grid.
I O
HO I
O H label
1.18 and 2.18 – remove bold from
H N H2
O1.18 and 2.18 – remove bold from label
I
Tri-iodo-L-thyronine
Tri-iodothyronine
Tri-iodothyronine
1.18 and 2.18 – from

5. T4 is biosynthesized remove bold from
L-tyrosine label the thyroglobulin molecule and is considered an amino
within
acid–based hormone. Other hormones in the body are steroid-based (e.g., estrogen) or peptide-
1.18 andEvaluate
based (e.g., insulin). 2.18 – remove bold from
the structure oflabel
T4 and justify its classification as an amino acid–based
O
hormone by determining which functional groups are derived from L-tyrosine.
I O
H 2N
OH O HO I
H I OH O
H 2N
OH HO I H NH
H 2 OH
I O
OH I H NH
2
I O
L-Tyrosine OH Levothyroxine I

H NH
2
I O I
I 1.18 Levothyroxine H
(TO
4
) 63 I
Levothyroxine
6. Interestingly, the dehalogenation transformation represents both an activation and deactivation I O
pathway for T4. The iodo substituents on the inner ring of T4 play a role not only in important hydro-
phobic binding interactions with the receptor, but also in maintaining the shape of the hormone in B
a perpendicular orientation (see diagram below). This perpendicular shape is necessary to appro-
priately position the phenolic OH to participate in key receptor binding interactions. Evaluate the
metabolites produced from the dehalogenation
1.18 and 2.18 – transformations and
structure was fixed identify
(pay which to
no attention metabolite
the colors)is
active and which is not. Provide a brief rationale for your answers.
I O
1.19 and 2.19 – remove bold from label.
HO I
OH
A H NH
2
C O
I
D A
I O
HO I
OH
H NH
B
2
I O I O
Lidocaine
I HO I
OH
Levothyroxine H NH
2
I O
1.18 and 2.18 – structure was fixed (pay no attention to the colors)
A
1.19 Lidocaine
As a sodium channel blocker, lidocaine has found therapeutic use both as a local anesthetic and as a Class IB anti-
arrhythmic agent. As an anesthetic, this agent demonstrates rapid onset of action (acts quickly) and a longer dura-
tion of action (lasts longer) than most amino ester-type local anesthetics. The most frequently observed side effects
are changes in the central nervous system (CNS) (e.g. dizziness, lightheadedness, tinnitus). Lidocaine is extensively
metabolized by the CYP1A2 isozymes to a variety of metabolites.
1. Conduct a complete structural evaluation of ow.

1. Conduct a complete structural evaluation of lidocaine, place your answers in the grid provided, and then
use the evaluation information in the grid to inform your answers to some of the questions that follow.
C H3 CH3
O
N C H3
N
C H3 H
Lidocaine
Lidocaine
Function
Character
Amino Acids That
Acidic, Function Can Interact with
4 Unless place next to the relevant arrow.
Basic, Interaction(s) the Functional
Character or Neutral Function Group via Hydrogen
Possible with
Name of Hydrophilic Provide ↑ Solubility Biological Target Bonding Interac-
Functional and/or pKa When and/or at Physiological tions at pH=7.4
2. Based on the information in the structure evaluation grid, determine whether or not lidocaine is likely
soluble in the blood (pH=7.4).
65
3. Local anesthetics that have a rapid onset of action are rapidly distributed in the body and can be
absorbed easily across lipophilic membranes. Based on the information in the structure evaluation
grid, provide a rationale for why lidocaine is rapidly distributed and can easily be absorbed across
lipophilic membranes.
4. Unless excreted unchanged, drug molecules undergo one or more metabolic transformations to
deactivate the drug and/or make the drug sufficiently water soluble to permit elimination. There are
a variety
1.19 of transformations
and 2.19 – remove bold fromthatlabels
are possible for most
and remove drugs,
answers butover
from onlythe
the minimum
arrows (pay number of trans-
no attention to
formations
the colors) actually occurs. The following diagram captures the metabolic pathways for lidocaine
that are observed clinically. For each transformation, identify which phase I metabolic transformation
has taken place next to the relevant arrow.
C H3 C H3
O
N C H3
N
C H3 H
Lidocaine
C H3 C H3
HO C H3 O H
O
N C H3
N C H3 N
N
C H3 H
C H3 H
Monoethylglycinexylidide
HO C H3
O H
N C H3
N
C H3 H C H3 C H3
O
N H2
3-Hydroxy-monoethylglycinexylidide
3-Hydroxy-monoethylglycineexylidide N H2 N
C H3 C H3 H
+
Glycinexylidide
O H
N C H3
HO
1.19 Lidocaine 67
5. Now that you have identified the metabolic transformations that generate products that have been
identified, put your detective hat on and list any additional phase I transformations that could have
occurred.
6. Lidocaine suffers from CNS-based toxicities largely due to production of the N-dealkylated metabolic
product monoethylglycinexylidide once the parent drug has crossed the blood–brain barrier.
a. Provide a structural rationale for why lidocaine is able to cross the blood–brain barrier.
b. Interestingly, neither
1.19 and 2.19 tolycaine
– remove nor
boldtocainide
from labeldemonstrates similar CNS-based toxicities. Provide a
structural rationale for why these two local anesthetics are devoid of CNS-based side effects.
Tolycaine Tolcainide

A
B C
D
Sitagliptin
Sitagliptin phosphate
1.20 Montelukast and Zafirlukast
Shown below are the structures of montelukast and zafirlukast. These drug molecules are administered orally for the
treatment of asthma and allergic rhinitis.
Montelukast
Zafirlukast
1. The structure of montelukast contains one acidic functional group (pKa=4.4) and one basic functional
group (pKa=3.1), whereas the structure of zafirlukast only contains one acidic functional group (pKa=4.3).
1. The
Identify structure
these of basic functional groups and predict whether they will be primarily ionized or
acidic and
primarily
2. In unionized
the use theatRule
a stomach
of NinespH=1.9, a urine
to calculate the pH=5.4, a cellular
percent of pH=6.1,
the functional a plasma
group pH=7.2,
that would and a solu-
be ionized.
tion pH=8.3.
3. The an explanation for this difference.
4. Montelukast and zafirlukast. Assume
Acidic or that allIonized
Primarily bindingorinteractions
Unionized occur at a physiological pH of 7.4.
Functional Group log P these hepatic
5. Calculated Basic 1.9
metabolism 5.4primarily excreted
or be 6.1 7.2
unchanged? 8.3
6. Shown below is to perform with zafirlukast.
2. In the previous question, we examined three pKa values in five different environments for a total of 15
different scenarios. Which of these 15 scenarios allow you to use the Rule of Nines to calculate the percent
of ionization of the functional group in the specific environment? Identify the specific scenarios and use
the Rule of Nines to calculate the percent of the functional group that would be ionized.
69
3. The sodium salt of montelukast is required for its oral administration, whereas zafirlukast can be
administered orally as its unionized free acid form. Conduct a structural analysis of these two drug
molecules and provide an explanation for this difference.
4. Montelukast and zafirlukast exert their mechanism of action by interacting with cysteinyl leukotriene
Montelukast
receptors and blocking the normal actions of endogenous leukotrienes (LTC4, LTD4, and LTE4). It has
been proposed that this interaction requires five key elements: an ionic interaction, a hydrogen bond
interaction where the antagonist acts as the acceptor, as well as the interaction of the antagonist
with three separate hydrophobic pockets within the receptor. Using this information and the struc-
tures of montelukast and zafirlukast, propose potential binding interactions between these drug
molecules and cysteinyl leukotriene receptors. Assume that all binding interactions occur at a physi-
ological pH=7.4. Zafirlukast
5. Calculated log P values of montelukast and zafirlukast lie in the range of 5.5 to 6.4 depending on the
computer program used to predict these values. Given this information, would these drug molecules
be
1. predicted to be
The structure ofhighly plasma protein bound or minimally plasma protein bound? Additionally,
would you expect these drug molecules to undergo extensive hepatic metabolism or be primarily
2. In theunchanged?
excreted use the Rule of Nines to calculate the percent of the functional group that would be ionized.
3. The an explanation for this difference.
4. Montelukast
6. Shown and structure
below is the zafirlukast.
ofAssume that and
zafirlukast all binding interactions
a list of occurtransformations.
five metabolic at a physiologicalFor
pH each
of 7.4.
metabolic transformation, indicate if it is a phase I or a phase II transformation and if zafirlukast has
5. Calculated log P these hepatic metabolism or be primarily excreted unchanged?
a functional group present that can participate in the transformation. If you answer YES, then draw
6. appropriate
the Shown belowmetabolite;
is to performifwith
youzafirlukast.
answer NO, then provide a brief explanation as to why this meta-
bolic transformation is not possible to perform with zafirlukast.
Metabolic Pathways
A. Methylation
B. Aromatic Oxidation
C. Hydrolysis
D. Oxidative O-Dealkylation
1.21 Phenobarbital and

Other Barbiturates
Shown below are the structures of butabarbital, secobarbital, and phenobarbital. These drug molecules are used as
1.21PhenobarbitalandOtherBarbiturates
sedative-hypnotic agents in the treatment of insomnia and inducing sedation prior to surgical procedures. Phenobar-

bital can be used in the treatment of a number of different seizure disorders. Their sedative properties are due to their
ability to interact
Shown belowwith
are the GABAA receptor
the structures in the central
of butabarbital, seconervous system (CNS).
O O O O O O
HN NH HN NH HN NH
O O O
Butabarbital Secobarbital Phenobarbital
1. Conduct a structural analysis of these drug molecules and provide an explanation as to why they can be
1. Conduct
administered a structural
orally analysis. previously listed.
for the indications
2. Butabarbital and as to why these two drug molecules need to be administered as their sodium salts.
2. Butabarbital and secobarbital are marketed as their sodium salts and phenobarbital is marketed in its free
acid form (i.e., non-salt form). Draw the sodium salt of either butabarbital or secobarbital and provide an
explanation as to why these two drug molecules need to be administered as their sodium salts.
3. Using the phenobarbital is a long-acting agent (= 30–60 minutes; duration = 10–16 hours).
3. Using
4. the information
Secobarbital in questions
contains 1 andor2unionized
an ionized and your answers to those questions,
at pH environments provide
of 1.5, 5.9, anand
6.3, 7.4, explanation
8.9.
as to why secobarbital is a short-acting agent (onset of action = 10–15 minutes; duration = 3–4 hours),
butabarbital is an intermediate-acting agent (onset of action = 45–60 minutes; duration = 6-8 hours), and
phenobarbital
5. As statedis aoflong-acting agent
the amino acids (onset of action = 30–60 minutes; duration = 10–16 hours).
indicated.
4. Secobarbital
6. Shown contains an ionizable
below. Would you to functional
retain their group with a pKactivity?
pharmacological a
=7.9. Using
Whythe table
or why shown below, identify
not?
the functional group, provide the normal pKa range for the functional group, and identify if the func-
tional group would be primarily ionized or unionized at pH environments=1.5, 5.9, 6.3, 7.4, and 8.9.

Functional Group Basic pKa Range 1.5 5.9 6.3 7.4 8.9
71
Metabolite of Metabolite of Metabolite of

5. As stated above, barbiturates exert their mechanism of action by interacting with the GABAA recep-
tors. Assume that the following amino acids are involved in this binding: Val, Phe, Ser, Asn, and Lys.
Using the functional groups present within the structure of secobarbital, identify five specific binding
interactions between secobarbital and the side chains of the amino acids indicated.
Chapters1.21and2.21
6. Shown below are known metabolites of butabarbital, secobarbital, and phenobarbital. Identify the
PleasereplacetheindicatedstructureinQuestion6inboth1.21and2.21(theonethatispartofthequestion)
metabolic transformations that are required to produce each metabolite and indicate if they are
phase I or phase II transformations. Would you expect any of these metabolites to retain their
withtheonebelow.Bothstructureshadanidenticalerror.
pharmacological activity? Why or why not?

butabarbital secobarbital phenobarbital
Chapter2.22
PleasereplacethestructurefortheanswertoQuestion3inChapter2.22withtheonebelow.
Intramolecular
Hydrogen Bond
Intramolecular
Hydrogen Bond
Pravastatin
Fluvastatin

1.22 Pravastatin and Fluvastatin

ShownShown
below are theare
below structures of pravastatin
the structures andhave
of groups fluvastatin. These drug molecules are used in the treatment of
been boxed.
various types of hyperlipidemia/dyslipidemias. A total of six functional groups have been boxed.
F
C
B
D
Pravastatin
Fluvastatin
1. Using the table below, identify the six boxed functional groups. For each of the functional groups you
1. indicate
identify, Using the table
if it below, or hydrophobic
is hydrophilic in explanation
or hydrophobic for Also
in character. your provide
response.
a brief explanation for your
2. The log P drug a structural explanation for the difference in these log P values.
response.
3. The normal pKa range for normal range.
Answer
4.Functional
Pravastatin,
Groupand as to how pravastatin
Name andorfluvastain
Hydrophilic inhibit HMG CoA reductase.
Hydrophobic
A
B
C
HMG CoA
D Reductase
E
F
HMG CoA Mevalonic Acid

2. The log P values of pravastatin and fluvastatin are 1.44 and 3.62, respectively. Conduct a structural analysis
of these drug molecules and provide a structural explanation for the difference in these log P values.
5. Shown below are the postulate a reason why this structural change results in a loss in activity.
3. The normal pKa range for carboxylic acids is 2.5 to 5. The pKa values for the carboxylic acids present within
the structures of pravastatin and fluvastatin are 4.21 and 4.56. Conduct a structural analysis and provide a
reason why these pKa values are at the high end of the normal range.
73
E
E
74 Pravastatin
Medicinal Chemistry Self Assessment Fluvastatin
Pravastatin
Fluvastatin
1. Pravastatin
4. Using the table
and below, or hydrophobic
fluvastatin in explanation for
exert their hyperlipidemic your response.
effects by inhibiting the enzyme HMG CoA
reductase.
2. The log As
1. PUsing shown
drug the below, HMG
table below,
a structural or hydrophobic
CoA
explanation reductase converts
in explanation
for the difference 3-hydroxy-3-methylglutaryl
forlog
in these your
P response.
values. CoA (HMG
CoA) to mevalonic acid. This conversion is required for the synthesis of cholesterol and acts as a
2. ThepK
3. primary
The normal logrange
P drugfora normal
structural explanation for the difference in these log P values.
range.
controla site for production of this endogenous steroid. Using the structures of HMG CoA,
3.
mevalonic The normal
acid, pK
pravastatin,
4. Pravastatin, and as to how a range
pravastatin andrange.
and for normal
fluvastatin, provide aninhibit
fluvastain explanation
HMG CoA as to how pravastatin and fluvastatin
reductase.
inhibit HMG CoA reductase.
4. Pravastatin, and as to how pravastatin and fluvastain inhibit HMG CoA reductase.
HMG CoA
Reductase
HMG CoA
Reductase

5. Shown below are the structures of fluvastatin and a conformationally restricted analog. The addition
5. of
Shown
anotherbelow are the
carbon postulate
atom and the a reason why this structural
conformational change
restriction resultsabolish
essentially in a loss
theintherapeutic
activity. activity
5. Shown
of fluvastatin. below
Using are the
these postulatepostulate
structures, a reasonawhy this structural
reason change results
why this structural changein aresults
loss inin
activity.
a loss in
activity.
Fluvastatin Conformationally
Fluvastatin RestrictedConformationally
Analog
of Fluvastatin
Restricted Analog
of Fluvastatin
6. Pravastatin is primarily
6. Pravastatin metabolized to its 3α epimer. This metabolite is completely inactive as an
is is inactive.
HMG CoA reductase inhibitor. Identify the metabolic transformations required to produce this
metabolite and provide an explanation as to why this metabolite is inactive.
3D epimer
1.23 Quinapril
1.23 Quinapril
Shown below is the structure of quinapril. It is an angiotensin converting enzyme (ACE) inhibitor that is used in the
Shown below is are identified.
treatment of hypertension and heart failure. Five functional groups are identified.
B
H3C
O O D
A O
H
N
N
C
C H3
O
OH
E
1. Using 1.
the Using
table the
below, if it is hydrophilic
tableidentify or hydrophobic
the five boxed in brief explanation
functional groups. For each of for
theyour response.
functional groups you
identified, indicate if it is hydrophilic or hydrophobic in character. Also provide
2. Using the ionized or unionized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1. a brief explanation for
your response.
3.
Answer
CH3
A O O
B O
C H
N
D N
E C H3
O
OH

2. Using the unmodified structure of quinapril and the following table, identify all of the acidic and basic
normal pK range for each functional group, and
functional groups present in the structure, provide the a
identify if each functional group would be primarily ionized or unionized at pH environments=1.5, 4.8, 6.3,
7.4, and 8.1.
4. Quinapril is a is administered orally instead of quinaprilat.
75
Chapter1.23 A O
H
N
PleasereplacethestructureforQuestion2inChapter1.23withtheoneshownbelow.(NOTE:Theanalogous
76 Medicinal Chemistry Self Assessment N
structureinChapter2.23isfine.) C
C H3
O
OH
E
1. Using the table if it is hydrophilic or hydrophobic in brief explanation for your response.
2. Using the ionized or unionized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
3.
CH3
O O
O
H
N
Acidic or Primarily Ionized
N or Unionized
Chapters1.23and2.23 C H3
O
OH

PleasereplacethestructuresforAngiotensinIandQuinaprilatinQuestion4forboth1.23and2.23withtheone
providedbelow.

3. Quinapril is a prodrug. It is administered as an oral tablet and converted in vivo to its active metabo-
lite,
4.quinaprilat.
Quinapril is Identify the metabolic
a is administered pathway
orally instead that converts quinapril to quinaprilat, and offer a
of quinaprilat.
reason why quinapril is administered orally instead of quinaprilat.
Leu
His
Phe
Quinapril Quinaprilat
Quinaprilat
Angiotensin I
R = Asp-Arg-Val-Tyr-Ile-His-Pro
4. Quinapril inhibits ACE. This enzyme is a relatively nonspecific dipeptidyl carboxypeptidase. It is a zinc

protease that converts angiotensin I, a decapeptide, to angiotensin II, an octapeptide. The peptide
cleavage is catalyzed by the zinc atom and is shown below. Quinapril, along with other ACE inhibi-
tors, is a tripeptide mimic that can interact with the enzyme resulting in enzyme inhibition rather
than hydrolysis. Using this information and the structures provided below, identify how quinapril can
interact with ACE. Assume that all drug binding interactions are occurring at a pH=7.4.
providedbelow. 1.23 Quinapril 77
5. Quinapril inhibits ACE. This at a pH of 7.4.
LeuLeu
HisHis
PhePhe
Quinaprilat
Quinaprilat
AngiotensinI I
Angiotensin
R = Asp-Arg-Val-Tyr-Ile-His

6. Shown below are in these pathways.
5. Shown below are four possible metabolic pathways for quinapril. Identify the metabolic transforma-
tions involved in these pathways.
A B
Quinapril
C D
6. Although it is possible for quinapril to undergo all of the above metabolic transformations, pathway
B is the major pathway. Other metabolites have been identified, but only at very low levels. Provide
an explanation for this finding.
1.24 Rivastigmine
1.24Rivastigmine
ShownShown
belowbelow
is the structure of rivastigmine.
is the structure Four of
of rivastigmine. its functional
Four groups
of its functional have been
groups have identified.
been identified.
C H3 C CH3 D
A H3C N O C H3
N
O C H3
B
Rivastigmine
1. Using the table

1. Using the table below, identify the four boxed functional groups. For each of the functional groups you
2. Based
identified, indicate if it induction.
on their is hydrophilic or hydrophobic in character. Also provide a brief explanation for
your response.
3. Rivastigmine is an e. Glutamic acid, with acetylcholine.
Answer
Labile
Functional ester
Group bond
Name Hydrophilic or Hydrophobic
A
B
C
D
2. Based on their electronic properties AND their relative positions in the molecule, identify if functional
groups A and B are electron withdrawing or electron donating. Additionally, identify if this effect is due
to resonance or induction. Rivastigmine
3. Rivastigmine is an acetylcholinesterase inhibitor. Inhibition of this enzyme prolongs the half-life of acetyl-
Acetylcholine
choline, allowing for higherbound to active site
concentrations of acetylcholine at muscarinic and nicotinic receptors. This
of acetylcholinesterase
action is useful in the treatment of Alzheimer’s disease, myasthenia gravis, and glaucoma. Shown below is
the structure of acetylcholine interacting with the active site of acetylcholinesterase. Glutamic acid, histi-
dine, and serineA.are involved
Conduct ainrivastigmine
the mechanism of esterhow
and indicate hydrolysis
it couldand can form
interact specific interactions with
with acetylcholinestase.
acetylcholine.
B. The serine explanation as to how rivastigmine inhibits acetylcholinesterase.
79
O C H3
1. Using the table B
80 2. Based on their
Medicinal Chemistry Self Assessment Rivastigmine
induction.
1. Using the table
2. Based on induction.
theirester
Labile bond
Labile ester bond
Rivastigmine
Acetylcholine bound to active site Rivastigmine

A. a Conduct
a. Conduct structurala rivastigmine and indicate and
analysis of rivastigmine how indicate
it could interact
how it with
could acetylcholinestase.
interact with acetylcholin-
Acetylcholine
esterase. bound to active site
B. The serine explanation as to how rivastigmine inhibits acetylcholinesterase.
b. The serine residue of acetylcholinesterase attacks the ester bond of acetylcholine causing hydro-
lysis and acetylation of the serine. A similar reaction occurs between the carbamate group of
A. Conduct
rivastigmine andathe
rivastigmine and indicate
serine residue; howwhile
however, it could interact with isacetylcholinestase.
acetylcholine a substrate of acetylcholin-
B.
esterase,The serine explanation
rivastigmine as to how
is an inhibitor. rivastigmine
Compare inhibits acetylcholinesterase.
the functional groups involved and provide an
explanation as to how rivastigmine inhibits acetylcholinesterase.
Intermediate in the hydrolysis of

acetylcholine Analogous intermediate formed with
rivastigmine

rivastigmine
1.24 Rivastigmine 81
4. Neostigmine is a structural analog of rivastigmine. Similar to rivastigmine, neostigmine is able to

interact with acetylcholinesterase and cause inhibition due to the presence of a carbamate functional
group. The primary differences between rivastigmine and neostigmine are their routes of admin-
istration and their therapeutic indications. Rivastigmine is administered orally in the treatment of
Alzheimer’s disease, whereas neostigmine is administered intramuscularly (IM) or subcutaneously
(SC) in the treatment of myasthenia gravis. Conduct structural analyses of these drug molecules and
4. Neostigmine
provide is a structural
an explanation analog
for these of es in routes
differences of administration.
in routes of administration and therapeutic indications.
4. Neostigmine is a structural analog of es in routes of administration.
4. Neostigmine is a structural analog of es in routes of administration.

+
Neostigmine Bromide
+
5. 5. Rivastigmine
Rivastigmine hashas a longer
a longer duration aNeostigmine
durationofofaction
longer Bromide
duration
than of action.A comparison of the structures of
neostigmine.
rivastigmine and neostigmine reveals that the carbamate + group present in rivastigmine is slightly
larger
5. than that has
Rivastigmine present
a in neostigmine.
longer duration of aUsing
longerthe mechanism
duration of action given in question 3, provide
of action.
Methyl Neostigmine Bromide
a reason why this structural difference results in a longer duration
Methylof action.
Methyl
Methyl
5. Rivastigmine has a longer duration of a longer duration of action.
Methyl
Ethyl
Methyl
+ Methyl
Methyl
Neostigmine Rivastigmine
Ethyl
+
6. EvaluationNeostigmine Rivastigmine
of the structure of rivastigmine ability to inhibit acetylcholinesterase.
Methyl
Ethyl
6. Evaluation of the structure+of rivastigmine ability to inhibit acetylcholinesterase.
para orientation
meta orientation
6. Evaluation ofNeostigmine
the structure of rivastigmine reveals that the aliphatic chain containing the tertiary
Rivastigmine
amine is located meta to the carbamate group. Similar orientations can be seen with neostigmine.
Using the information from the previous questions, provide an explanation as to why a para orienta-
para orientation
6.
tionEvaluation of the meta
of these functional orientation
structure of rivastigmine
groups would leadability to inhibit acetylcholinesterase.
to a significant decrease in the ability to inhibit acetyl-
cholinesterase.
meta orientation para orientation

Rivastigmine para Analog of
Rivastigmine

Rivastigmine

Rivastigmine
1.25 Sitagliptin
Sitagliptin is an inhibitor of dipeptidyl peptidase IV (DPP-IV), a serine protease that catalyzes the deactivation/degra-
1.25 Sitagliptin
dation of GLP-1. GLP-1 is a 36-amino acid peptide that is responsible for promoting insulin secretion in response to
an increase in blood
Sitagliptin is anglucose
inhibitorlevels. Currently there are four DPP-IV inhibitors on the market, all of which contain an
of dipeptidyl
essential basic amino functional group that represents the penultimate amino-terminal alanine residue found within
GLP-1.
A
F
B C
F
N H2 O
D
N
N
N
F N
CF3
Sitagliptin
Sitagliptin
1. Conduct a structural evaluation of sitagliptin, focusing on the boxed functional groups and use the infor-
mation
1. inConduct
the gridato
toinform your answers
the questions to the questions that follow.
that follow.
2. Sitagliptin is salt form. Function

Function Amino Acids That Can
Character
Interaction(s) Interact with the Func-
Character Acidic, Basic, Function tional Group via Ion–
F Possible with
Name of Hydrophilic or Neutral
↑ Solubility Biological Target Dipole Interactions at
and/or F Provide pK pH=7.4
Functional a N and/or
H2 O at Physiological
A N
N
N
B
F N
C
CF3
D
Sitagliptin
3. Sitagliptin is designation.
4. At 38%, the bound (e.g., warfarin).
5. Approximately.
6. Assess each of ransformation has occurred.

83
84 1.Medicinal
Conduct Chemistry
a to theSelf Assessment
questions that follow.
2. Sitagliptin is salt form.

2. Sitagliptin is formulated as a phosphate salt. Identify the most basic functional group and modify the
structure to show the phosphate salt form.
F
F
N H2 O
N
N
N
F N
CF3
Sitagliptin
Sitagliptin
3. Sitagliptin is marketed as the R-enantiomer. Evaluate the structure of sitagliptin and provide a struc-
3. rationale
tural Sitagliptin is the
for designation.
R-enantiomer designation.
4. At 38%, the bound (e.g., warfarin).
4. At 38%, the fraction of sitagliptin reversibly bound to plasma proteins is relatively low. By way of
5. Approximately.
reminder, only the unbound fraction of drug is able to exert its biological activity and undergo
metabolism. Describe the relative risk of a plasma protein binding interaction between sitagliptin
6. Assess each of ransformation has occurred.
and another drug that is highly protein bound (e.g., warfarin).
5. Approximately 79% of sitagliptin is excreted unchanged in the urine. Provide a structural rationale
that supports this observation.
1.25 Sitagliptin 85
6. Assess each of the possible metabolic products generated from sitagliptin and determine which
phase I metabolic transformation has occurred.
C
D
1.26 Sorafenib
Because protein tyrosine kinases regulate cellular proliferation, differentiation, and survival, it is no surprise that
several neoplastic disorders can be tied to altered activity of protein tyrosine kinases. Clinically relevant antineo-
plastic tyrosine kinase inhibitors interact with the active site of the enzyme via several types of binding interactions.
The adenosine triphosphate (ATP) binding domain of the tyrosine kinases contains a hydrophobic domain that
includes a significant number of isoleucine, leucine, alanine and valine residues. There are at least five binding pockets
that flank this region in which van der Waals, hydrophobic, hydrogen bonding, and electrostatic interactions occur.
Sorafenib
1.26isSorafenib
a tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma, a highly vascularized
tumor. The drug specifically targets vascular endothelin growth factor 2 (VEGF2) that is instrumental in the genera-
tion ofBecause
new bloodprotein tyrosine kinases regulate
vessels.
C F
E
B D
Sorafenib
Sorafenib
1. Conduct a structural evaluation of sorafenib, focusing on the boxed functional groups, and use the infor-
1. Conduct a structural to the questions that follow.
mation in the grid to inform your answers to the questions that follow.
2. Sorafenib interacts in the local environment
Character of the enzyme. Function
Character298 299Acidic,
359Basic, Function
3. Nilotinib, another and Leu /Val /Phe in each of the respective five Interaction(s)
binding pockets.
Hydrophilic or Neutral ↑ Solubility Possible with Biological
Name of A
and/or Provide pKa and/or Target at Physiological
Functional Group Hydrophobic When Relevant ↑ Absorption pH=7.4
A
B C D E
B
Nilotinib
A. Consider the side chains of the the five binding pockets. Assume pH=7.4.
87
B. Determine acid side chains are both at pH=7.4.
2. Sorafenib interacts with Cys919, Phe1047, and Asp1046 via hydrogen bonding and hydrophobic interactions.
1.26 Sorafenib
Identify which functional groups could interact with the side chains of these amino acids. Assume
that Asp1046 is unionized in the local environment of the enzyme.
Because protein tyrosine kinases regulate
Interacts with Cysteine919 Interacts with Aspartic Acid1046
via a Hydrogen Bonding C via a Hydrogen Bonding F Interacts with Phenylalanine1047
Interaction Interaction via a Hydrophobic Interaction
Functional E
A
A
B
C
D B D
E
F Sorafenib
1. Conduct a structural to the questions that follow.

3. Nilotinib, another tyrosine kinase inhibitor (via Bcr-Abl) indicated for the treatment of Philadel-
2. Chromosome
phia Sorafenib interacts in the local
(Ph+) positive chronicenvironment of the enzyme.
myelogenous leukemia, also interacts with each of the five
binding pockets found within this 298
biological
299
target.
359
This drug interacts with Leu285/Val289, Asp391/Glu286,
3.
315 Nilotinib,
318 another
298and 299
Leu
Thr , Met and Leu /Val /Phe in each of the respectiverespective
/Val
359 /Phe in each of the fivepockets.
five binding binding pockets.
B C D E
Nilotinib
Nilotinib
a. Consider the side chains of the amino acids indicated and determine which type(s) of binding
A. Consider
interactions the side
are possible chains
in each ofofthe
thefive
the binding
five binding pockets.
pockets. Assume
Assume pH=7.4.
pH=7.4.
Leu285/Val289 Asp391/Glu286 Thr315 Met318 Leu298/Val299/Phe359
C. It has been participate in this interaction.
b. Determine which of the boxed functional groups (A–E) can interact with the side chains of the
amino acids found in each of the five binding pockets. Indicate the type of interaction(s) possible
in the appropriate box. None is an acceptable answer. Assume that the drug and the amino acid
side chains are both at pH=7.4.

A
B
C
D
E Methionine
Nilotinib
A. Consider the side chains of the the five binding pockets. Assume pH=7.4.
1.26 Sorafenib 89
c. It hasC.
beenIt has been participate
documented in this
that the interaction.
pyridyl nitrogen atom (functional group E) of nilotinib partici-
pates in a hydrogen bonding interaction with methionine. Draw a diagram that clearly shows
which atom(s) within the structure of methionine participate in this interaction.
Methionine
Methionine
4. Sorafenib enters cells via passive diffusion. Using the information in the structure evaluation grid as a
starting point, identify which functional groups contribute to the ability of this drug to enter cells via
passive diffusion.
5. Nilotinib is considered significantly more hydrophobic than sorafenib (distribution coefficient log D is
2.4 and 0.8 respectively). Provide a structural rationale for this property difference.
6. Sorafenib is marketed as a tosylate salt, a lipid-soluble organic salt. Nilotinib is marketed as a hydro-
chloride monohydrate salt, an inorganic salt. In general, what is the value of each of these types of
salts?
1.27 Zanamivir and Oseltamivir
1.27ZanamivirandOseltamivir
Shown below is the structure of zanamivir. This drug molecule is administered via oral inhalation for the treatment of
Shown below is the d B infections.
influenza A and B infections.
Zanamivir
1. Identify
1. Identify all of
all of the the H
acidic of 7.2.
and basic functional groups, provide the normal pKa range for each functional
group, and identify if each functional group would
2. Identify all other water soluble functional bethat
groups primarily ionized
are present or unionized
within at of
the structure a pulmonary
zanamivir.
pH=7.2.
3. Based on your or capsule.
4. Zanamivir exerts its n. Using neuraminidase.
2. Identify all other water soluble functional groups that are present within the structure of zanamivir.
3. Based on your answers to questions 1 and 2, explain why zanamivir is administered as an oral inhaler
instead of an oral tablet or capsule.
4. Zanamivir exerts its antiviral action by inhibiting neuraminidase, a viral enzyme that is required for the
spread of the viral infection. A key component of neuraminidase’s action is the hydrolysis of N-acetylsialic
acid from surface viral glycoproteins. Shown below is the structure of N-acetylsialic acid bound to a glyco-
protein. Using this structure Glycosidic
and the structure
bond of zanamivir, provide an explanation of how zanamivir
inhibits neuraminidase.
N-Acetylsialic acid bound to glycoprotein Zanamivir
5. Shown below is a, or similar to that of zanamivir?
91
1. Identify all of the H of 7.2.
3. Based on your or capsule.
92 Medicinal
3. Based on yourChemistry Self Assessment
or capsule.
4. Zanamivir exerts
Zanamivir
its n. Using neuraminidase.
4. Zanamivir exerts its n. Using neuraminidase.
of the H of 7.2.
other water soluble functional groups that are present within the structure of zanamivir.
our or capsule.
xerts its n. Using neuraminidase.
Glycosidic bond
Glycosidic bond
5. Shown
5. Shown below
below is is a, or similar
a stereoisomer to that ofIdentify
of zanamivir. zanamivir?
if the stereoisomer is an enantiomer, a diastereomer,
5. aShown below
geometric isomer, similar
is a, oran to that
epimer, of zanamivir?
and/or a conformational isomer. Predict whether this stereoisomer’s
pharmacological activity is likely to be more active, less active, or similar to that of zanamivir?
Glycosidic bond
alic acid bound to glycoprotein Zanamivir
w is a, or similar to that of zanamivir?
6. Shown below is the oseltamivir .

6. Shown below is the oseltamivir .
6. Shown below is the structure of oseltamivir and a list of five metabolic transformations. For each
metabolic transformation, indicate if it is a phase I or a phase II transformation and if oseltamivir has
a functional group present that can undergo the indicated transformation. When evaluating these
metabolic transformations, consider functional groups that are initially present within the structure
of oseltamivir as well as those that can be added/revealed through phase I metabolism. If you answer
YES, .then draw the appropriate metabolite; if you answer NO, then provide a brief explanation as to
w is the oseltamivir
why this metabolic transformation is not possible for oseltamivir.
Metabolic Pathways
A. Hydrolysis
B. Allylic oxidation
C. Glucuronide conjugation
D. ω-Oxidation
E. Oxidative O-Dealkylation
Part 2 ANSWERS
Section 3 – General Self Assessment

2.1 Functional Group Characteristics and Roles................... 95
2.2 Identifying Acidic and Basic Functional Groups.............. 99
2.3 Solving pH/pKa Problems.............................................. 105
2.4 Salts and Solubility....................................................... 109
2.5 Drug Binding Interactions............................................ 113
2.6 Stereochemistry and Drug Action................................. 117
2.7 Drug Metabolism......................................................... 123
Section 3 General Self Assessment Answers
Structures for 1.1 and 2.1

2.1 Functional Group Characteristics
The bold has been removed.
and Roles
The exact same structures are in both of these chapters, but I have provided two
copies in the event you wanted that.
1. Shown below are the structures of warfarin, phenytoin, bromfenac, and salmeterol.
a. Identify each of the boxed functional groups.
A
F
D
Warfarin G
B Bromfenac
Phenytoin
H
J K
I L
Salmeterol
Answer
Box Functional Group Name

A β-Dicarbonyl (enol form)
B Ketone D
B
C A Phenyl ring; aromatic ring; aromatic hydrocarbon O
O C C H3
D Imide
H 2N S N
E Halogen (bromo) OH H O
N
F Primary aromatic amine; aniline O
G Carboxylic acid Sulfamethoxazole
Ibuprofen
H Primary hydroxyl group or primary alcohol
I Phenol or phenolic hydroxyl group
J Secondary amine
K Alkyl chain; aliphatic alkane
L Ether
95
b. For each of the functional groups you identified, indicate if it is hydrophilic or hydrophobic in
Structures for 1.1 and
character. Also2.1
provide a brief explanation for your response.
Answer
The bold has been removed. The exact same structures are in both of these chapters, but I have provided two
Box Hydrophilic or Hydrophobic
copies in the Aevent youAcidic
wanted that.group; hydrophilic due to its ability to ionize and ability to participate in hydrogen bonding in its
functional
unionized form.
B Hydrophilic due to its ability to act as a hydrogen bond acceptor.
C Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional groups enhance lipid
solubility.
D A Acidic functional group; hydrophilic due to its ability to ionize and ability to participate in hydrogen bonding in its
unionized form. F
E Hydrophobic due to its inability to ionize or form hydrogen bonds.
C
F Weakly basic functional group; hydrophilic primarily due to its ability to form hydrogen bonds, although it is
possible for this functional group to be ionized. If unionized, primary aromatic amines can act as hydrogen bond
donors and acceptors. E
G Acidic functional group; hydrophilic due to its ability to ionize and ability to participate in hydrogen bonding in its
unionized form. D
Warfarin G
H Hydrophilic
B due to its ability to form hydrogen bonds; can act as both a hydrogen bond donor and acceptor.
Bromfenac
I Phenytoinprimarily due to its ability to form hydrogen bonds. If unionized,
Weakly acidic functional group; hydrophilic
phenolic hydroxyl groups can act as hydrogen bond donors and acceptors.
J Basic functional group; hydrophilic due to its ability to ionize and ability to participate in hydrogen bonding in its
unionized form.
K Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional groups enhance lipid
H solubility.
L J
The ether oxygen atom is hydrophilic due to its ability to act as a hydrogen bond acceptor; however, due to
K
I hydrocarbon surrounding this ether on L chain attached to the secondary amine could be
both sides, the entire side
classified as primarily hydrophobic.
Salmeterol
2. Shown below are the structures of ibuprofen and sulfamethoxazole. Four functional groups have
been highlighted. Based on their electronic properties AND their relative positions in the molecule,
identify if they are electron withdrawing or electron donating. Additionally, identify if this effect is
B D
A O C H3
O C
H 2N S N
OH H O
N
O
Ibuprofen Sulfamethoxazole
Answer
Functional group A: This is an alkyl group (aliphatic chain). Because it is directly attached to an
aromatic ring, it can act as an electron donating group through induction.
Functional group B: This is a carboxylic acid that will most likely be ionized at physiological pH and
carry a negative charge. Therefore, it can be electron donating through induction.
Functional group C: This is an aniline (or primary aromatic amine). Because the nitrogen atom is
directly attached to the aromatic ring, it acts as an electron donating group through resonance.
This electron donating property is responsible for the low basicity of aromatic amines (discussed in
Chapter 3*).
2.1 Functional Group Characteristics and Roles 97
Functional group D: This is a heterocyclic aromatic ring. It is electron withdrawing due to induction.
This electron withdrawing property is responsible for the increased acidity of the adjacent sulfon-
amide (discussed in Chapter 3*).
3. Shown below is the structure of imipramine as well as three analogs. Evaluate each analog and
provide an overall evaluation of how each change will affect the chemical properties of imipramine.
Imipramine
Analog A Analog B Analog C
Answer
Analog A: In this analog, a chlorine atom has replaced a hydrogen atom. A hydrogen atom generally
does not contribute to electronic and solubility properties. Additionally, it is the smallest atom and
thus sterically occupies the least amount of space. In contrast, the chlorine atom is electron with-
drawing in character, enhances the overall lipid solubility of imipramine, and sterically is larger than
the original hydrogen atom.
Analog B: Similar to Analog A, this analog occurs via the replacement of a hydrogen atom with
another functional group. The alkyl chain (propyl chain) is electron donating, enhances the overall
lipid solubility of imipramine, and is sterically much larger than the original hydrogen atom.
Analog C: In this analog, a methyl group has been replaced by an acetyl group that converts the
tertiary amine to an amide. The methyl group is electron donating and contributes to the basicity
of the tertiary amine. In contrast, the carbonyl group is electron withdrawing. This significantly
decreases the availability of the lone pair of electrons on the nitrogen atom such that it is no longer
basic. In terms of solubility, the substitution of the acetyl group for the methyl group decreases water
solubility. This is because the nitrogen atom is no longer basic and thus cannot undergo ionization.
The resulting amide is water soluble due to its ability to act as a hydrogen bond acceptor; however,
the change from a functional group that can ionize to one that can only participate in hydrogen
bonding results in an overall decrease in water solubility. Finally, the acetyl group is sterically larger
than the original methyl group.
4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side chains of the
four amino acids have been boxed.

4. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The side
chains of the four amino acids have been boxed.
a. Identify the four amino acids that comprise this tetrapeptide sequence.
Answer
Tyrosine (Tyr)—Aspartic Acid (Asp)—Valine (Val)—Glutamine (Gln)
b. For each amino acid, identify the key chemical properties of its highlighted side chain.
Answer
Tyrosine: This side chain is one of the largest seen in amino acids and is involved in dictating
Page2of2
the overall conformation of the peptide. Although the phenyl ring is hydrophobic, the phenolic
hydroxyl group can act as both a hydrogen bond donor and acceptor and contributes to the
overall water solubility.
Aspartic Acid: This side chain is acidic and will most likely be ionized at physiological pH. This will
enhance the overall water solubility of the peptide. It will most likely reside in a water soluble
pocket of the overall peptide.
Valine: This is an aliphatic, lipid soluble, hydrocarbon side chain. It contributes to the overall lipid
solubility of the peptide and can contribute to lipid soluble pockets within the peptide. Addition-
ally, the isopropyl side chain can impart some steric bulk that may influence the overall conforma-
tion of the molecule.
Glutamine: Overall, this side chain is normally classified as a polar, water soluble side chain due to
its ability to act as both a hydrogen bond donor and acceptor. The two methylene carbon atoms
allow the amide to be oriented in different locations and may contribute a little to the overall
lipid solubility of the peptide.
Go to Section 1.3 [Link to section 1.3 title]

2.2 Identifying Acidic and Basic

2.2
Functional Groups
groups.
groups.
Answer
2 3
4
8
6
Sorbinil
Answer:
Drug Name Acidic Functional Groups Basic Functional Groups
As discussed in Chapter 3*, there are two key structural features of an acidic functional group. The first is the
Experimental Oral Anticoagulant Sulfonamide (2) Amidine (1)
presence of a proton (H+) that can leave (i.e., dissociate), and the second is the presence of adjacent atoms that
Bromfenac Carboxylic acid (4) Aromatic amine or aniline (3)
acid and an imide are acidic, while
Sorbinil functional groups such as secondaryNone
Imide (5) hydroxyl groups (i.e., secondary
Experimental
alcohols)Antidiabetic
and thiolsAgent
are neutralPhenol (6)
functional groups. Secondary amine (8)
Sulfonamide (7)
Resonance stabilization No resonance available

of resulting negative charge if proton would leave
99
Sorbinil
100 Medicinal Chemistry Self Assessment Experimental antidiabetic agent
2. Using any one of the acidic functional groups that you identified in question 1, provide an explana-
Answer:
tion as to why the functional group is acidic. Also provide a similar type of analysis for any one of the
basic functional groups that you identified in question 1.
As discussed in Chapter 3*, there are two key structural features of an acidic functional group. The first is the
Answer
presence of a proton
As discussed (H+) that 3*,
in Chapter canthere
leave are
(i.e.,two
dissociate), and the
key structural secondof
features is an
the acidic
presence of adjacent
functional atoms
group. Thethat
first is the presence of a proton (H ) that can leave (i.e., dissociate), and the second is the presence
+
acid and an imideatoms

of adjacent are acidic,
that while functional
are able to share groups such as secondary
the resulting hydroxyl
negative charge groups resonance.
through (i.e., secondary
Hence,
functional groups such as a carboxylic acid and an imide are acidic, while functional groups such as
alcohols) and thiols
secondary are neutral
hydroxyl groupsfunctional groups. alcohols) and thiols are neutral functional groups.
(i.e., secondary
Resonance stabilization No resonance available

of resulting negative charge if proton would leave
Carboxylic Secondary
Imide Hydroxyl Sulfhydryl
Acid
For basic functional groups, the key structural feature is a nitrogen atom that has a lone pairPage1of5
of
nonbonding electrons that can accept a proton (H +
). The relative ability of the electrons on different
nitrogen-containing functional groups determines their relative basicity. Thus, amidines and
secondary amines are basic, while amides are not.
For basic functional groups, the key structural feature is a nitrogen atom that has a lone pair of nonbonding
amides are not.
Resonance with
adjacent carbonyl greatly
decreases availablity of electrons
Amidine Secondary
amine Amide
3. Using the structures from question 1, modify all of the acidic functional groups to show their ionized forms and
in the table below identify the normal pKa range for the specific functional group.
Answer:
_
amine Amide
2.2 Identifying Acidic and Basic Functional Groups 101

3. Using the structures from question 1, modify all of the acidic functional groups to show their ionized forms and
in3.
theUsing
table the
below identify the
structures normal
from pKa range
question for the
1, modify all specific functional
of the acidic group. groups to show their ionized
functional
forms and in the table below identify the normal pKa range for the specific functional group.
Answer:
Answer
Sorbinil
Drug Name Acidic Functional Group Normal pKa Range
Experimental Oral Anticoagulant Sulfonamide pKa=5 to 10
Bromfenac Carboxylic acid pKa=2.5 to 5
Sorbinil Imide pKa=4.5 to 8.5 (generally on the higher end,

7.0 to 8.5)
Experimental Antidiabetic Agent Phenol pKa=9 to 10

Sulfonamide pKa=5 to 10
Page2of5

4. UsingMedicinal
102 the structures from Self
Chemistry question 1, modify all basic functional groups to show their ionized forms and in the
Assessment
table below identify the normal pKa range for the specific functional group.
4. Using the structures from question 1, modify all basic functional groups to show their ionized forms
Answer:
and in the table below identify the normal pKa range for the specific functional group.
Answer
OCH3
+
O H 2N O NH3
+ O
H2 N O S
O OH
NH2 N O N O
H Br
O
H
N
HN O
F
O O
H +
N S N
N H2
O HO H
N
N
Sorbinil
Drug Name Basic Functional Group Normal pKa Range

Experimental Oral Anticoagulant Amidine pKa=10 to 11
Bromfenac Aromatic amine (aniline) pK =2 to 5

5. Shown below is the structure of clonidine, an D adrenergic agonist that can abe used to treat hypertension.
Sorbinil None Not applicable
Experimental Antidiabetic Agent Secondary amine pKa=9 to 11
functional groups, such as that seen with arginine are much more basic with a pKa of 12.5. Provide a chemical
5. Shown below is the structure of clonidine, an α2 adrenergic agonist that can be used to treat hyper-
explanation for this
tension. difference.
Clonidine contains a guanidine functional group (highlighted in bold) that has a pKa=8.3.
Other guanidine functional groups, such as that seen with arginine, are much more basic with a
pKa=12.5. Provide a chemical explanation for this difference.
pKa = 12.5
pKa = 8.3
Clonidine Arginine
Answer
Answer:Unlike the side chain of the amino acid arginine, the guanidine group of clonidine is directly
attached to an aromatic ring. As such, the nitrogen atom directly attached to the aromatic ring
(highlighted
Unlike the side chainbelow) can donate
of the amino electrons
acid arginine, theinto the aromatic
guanidine group ofring, thus making
clonidine it attached
is directly less available
to an for
resonance stabilization of a positive charge. In addition, the aromatic ring of clonidine is attached to
two
aromatic ortho
ring. chloro
As such, thegroups. Each
nitrogen ofdirectly
atom these halogens is electron
attached to withdrawing
the aromatic and further
ring (highlighted below)decreases
can donate the
basicity of the guanidine group. The combination of these two effects decreases the basicity of the
guanidine
electrons group byring,
into the aromatic greater
thus than four
making orders
it less of magnitude.
available for resonance stabilization of a positive charge. In
Page3of5

addition, the aromatic ring of clonidine is attached to two ortho chloro groups. Each of these halogens is electron
withdrawing and further decreases the basicity of the guanidine group. The combination of these two effects
2.2than
decreases the basicity of the guanidine group by greater Identifying Acidic
four orders of and Basic Functional Groups
magnitude. 103
Involved in resonance
Cl with aromatic ring
H H
N N
N
Cl
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug molecule,
Clonidine
an amphoteric drug molecule, or a nonelectrolyte.
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug
Answer:
molecule, an amphoteric drug molecule, or a nonelectrolyte.
Answer
Basic Acidic
O NH O COOH
CF3
N
H Basic H 2N N N
H
O NH
N S CH3
O H
Acidic N Basic
N O
Lomitapide H
CF3
C H3
Argatroban Page4of5
Acidic
HO OCH3
COOH
OH
O
H O NH
H3C O Cl N S
H N N H2
C H3 C H3 H O CH3
H 2N N NH2 Basic N
O O
HO
Amiloride CH2 N(CH3 )2 Basic
Pravastatin
Diltiazem
Drug Molecule Acid/Base Character of Drug Molecule
Lomitapide Basic: Contains only a basic tertiary amine
Argatroban Amphoteric: Contains two acidic functional groups (a carboxylic acid and a sulfonamide) and two basic func-
tional groups (a guanidine group and an aromatic amine)
Pravastatin Acidic: Contains only an acidic carboxylic acid
Amiloride Basic: Contains a basic guanidine group as well as a basic aromatic heterocyclic ring (pyrazine)
Diltiazem Basic: Contains only a basic tertiary amine

2.3 Solving pH/pKa Problems
Chapter 3
Solving pH/pK
molecules a Problems
contains one ionizable functional group. The pKa values have been provided.
a. Match the pKa values provided with the appropriate functional groups. For each functional group,
1. Shown below the
identify are name
the structures of cefotaxime,
of the group nitrofurantoin,
and whether atenolol,
it is acidic and ezetimibe. Each of these drug
or basic.
molecules
b. For contains one ionizable
each functional groupfunctional
indicategroup. TheitpK
whether a values
would behave been provided.
primarily ionized or primarily unionized at a
stomach pH=1.8, a urinary pH=6.1, or a plasma pH=7.4. Provide an explanation for your responses for
Answer:
cefotaxime at a plasma pH=7.4, nitrofurantoin at a urinary pH=6.1, and atenolol at a stomach pH=1.8.
Answer
Imide
Acidic
Cefotaxime Nitrofurantion
Nitrofurantoin
pKa = 3.4 Carboxylic acid pKa = 7.1
Acidic
Aromatic
hydroxyl
(phenol)
Secondary amine
Acidic
Basic
Atenolol
pKa = 9.6 Ezetimibe
pKa = 10.2
Cefotaxime contains an acidic carboxylic acid. At a plasma pH=7.4, the environment (i.e., the pH) is more
basic than the functional group (i.e., the pH > pKa). An acidic functional group will be primarily ionized in
a basicbelow
3. Shown environment.
is the structure of natamycin. It contains two functional groups that could be potentially ionized.
Nitrofurantoin contains an acidic imide group. At a urinary pH=6.1, the environment (i.e., the pH) is more
acidic than the functional group (i.e., the pH < pKa). An acidic functional group will be primarily unionized
in an acidic environment.
Atenolol contains a basic secondary amine. At a stomach pH=1.8, the environment (i.e., the pH) is more
acidic than the functional group (i.e., the pH <OpKa). A basicOfunctional
H group will be primarily ionized in
O OH
an acidic environment.
H3C O OH O
COOH
105
Answer:
Imide
Acidic
Drug (pKa Value) Stomach (pH=1.8) Urine (pH=6.1) Plasma (pH=7.4)
Cefotaxime (3.4) Primarily unionized Primarily ionized Primarily ionized
Nitrofurantoin (7.1) Primarily unionized Primarily unionized Primarily ionized
Cefotaxime
Atenolol (9.6) Primarily ionized Primarily ionized Nitrofurantion
Primarily ionized
pKa = 3.4
Ezetimibe (10.2) Carboxylic acid
Primarily unionized Primarily unionized a
= 7.1unionized
pKPrimarily
Acidic
2. In the previous question, we examined four pKa values in three different environments for a total
Aromatic
of 12 different scenarios. Which of these 12 scenarios allow you to use the Rule of Nines to calculate
hydroxyl
scenarios and use the Rule of Nines
Secondary to calculate the percent of the functional group that would(phenol)
amine be
ionized. Acidic
Basic
Answer
Atenolol
To use the Rule of Nines, pK the =difference
9.6 between the pH and the pK must be an integer (i.e., 1,
Ezetimibe
a
a
2, 3). In evaluating the above 12 scenarios, there are only two scenarios pK = that
10.2 meet this criterion,
cefotaxime (pKa=3.4) in a plasma pH=7.4 and nitrofurantoin (pKa=7.1)a in a urinary pH=6.1. For cefo-
taxime, |pH – pKa| is equal to 4; thus, there is a 99.99:0.01 ratio. Because the carboxylic acid (pKa=3.4)
would be primarily ionized in a basic environment (pH=7.4), we can use this ratio to determine that
it would be 99.99% ionized. For nitrofurantoin, |pH – pKa| is equal to 1; thus, there is a 90:10 ratio.
The imide (pKa=7.1) functional group is acidic, so it would be primarily unionized in an acidic environ-
ment
3. Shown (pH=6.1).
below We can use
is the structure this information
of natamycin. to predict
It contains that it would
two functional groups be
that10% ionized.
could be potentially ionized.

3. Shown below is the structure of natamycin. It contains two functional groups that could be poten-
tially ionized. The pKa values for natamycin are 4.6 and 8.4.
O OH
O OH
H3C O OH O
COOH
O O C H3
Natamycin
HO OH
N H2
a. Match the pKa values provided to the appropriate functional groups and identify if the functional
group is acidic or basic.
b. Using the Henderson-Hasselbalch equation, calculate the percent ionization that occurs for each
Page1of2
of these functional groups at an intestinal pH=6.2.
each of these functional groups at an intestinal pH of 6.2.
2.3 Solving pH/pKa Problems 107
Answer:
Answer
a.
O OH
O OH
H3C O OH O Carboxylic acid

COOH
(pKa = 4.6)
Acidic
O O C H3
Natamycin
HO OH
N H 2 Primary amine
(pKa = 8.4)
Basic
b. For the carboxylic acid, the pKa=4.6 and the pH=6.2. Using the Henderson-Hasselbalch equation
gives the group
4. The most basic functional following:
present within the structure of ranitidine has a pK value of 8.2. Identify this
a
functional group and calculate the [Base Form]

6.2 = 4.6 +log pH that is necessary for this functional group to be 70% ionized.
[Acid Form]
Answer:
Solving the equation provides a ratio of [Base Form]/[Acid Form].
[Base Form] The electron withdrawing property of the nitro

1.6 = log
[Acid Form] group greatly decreases the pKa value for the
[Base Form] 39.8 [Base Form] adjacent nitrogen containing group.

39.8 = or =
amine [Acid Form] 1 [Acid Form]
Tertiary
pKa = 8.2 Ranitidine
For every molecule that contains this functional group in the acid form, there are 39.8 molecules that
contain this functional group in the base form. Because the functional group is acidic, the base form
is equal to the ionized form, and the acid form is equal to the unionized form.
39.8 molecules in base form + 1.0 molecule in acid form = 40.8 Total Molecules
Base Form = Ionized Form, and Acid Form = Unionized Form for This Functional Group
39.8 Molecules in Ionized Form
Percent in Ionized Form = x 100%
40.8 Total Molecules
Percent in Ionized Form= 97.5%
For the primary amine, the pKa=8.4 and the pH=6.2. Using the Henderson-Hasselbalch equation gives
the following:
[Base Form]
6.2 = 8.4 +log
[Acid Form] Page2of2

Answer:
Solving the equation provides a ratio of [Base Form]/[Acid Form].

O OH
O OH
[Base Form]
−2.2 = log
[Acid Form]H 3 C O OH O Carboxylic acid
COOH
[Base Form] 0.0063 [Base Form] (pKa = 4.6)
0.0063 = or = Acidic
[Acid Form] 1 [Acid Form]
O O C H3
For every molecule that contains this functional group in the acid form, there are 0.0063 molecules
Natamycin
that contain this functional group in the base form. Because the functional group is basic, the base
form is equal to the unionized form, and the acid formHisOequal to theOionized
H form.
0.0063 molecules in base form + 1.0 molecule in acid form = 1.0063
N H 2 Total Molecules
Primary amine
(pKa = 8.4)
Base Form = Unionized Form, and Acid Form = Ionized Form for This Functional
Basic Group
1 Molecule in Ionized Form
Percent in Ionized Form = x 100%
4. Percent in Ionized Form
The most basic functional = 99.4%
group present within the structure of ranitidine has a pKa value of 8.2. Identify this
4. Answer:
The most basic functional group present within the structure of ranitidine has a pKa=8.2. Identify this
Answer
The electron withdrawing property of the nitro
group greatly decreases the pKa value for the
The electron withdrawing property of the nitro
adjacent
group nitrogen
greatly containing
decreases group.
the pKa value for the
adjacent nitrogen-containing group.
Tertiary amine
pKa = 8.2 Ranitidine
We can use the Henderson-Hasselbalch equation to solve this problem. Because the ionized form of
a basic functional group can also be designated as its protonated form or its conjugate acid form,
either of the following equations can be used.
[Base Form]
pH = pK a +log
[Acid Form]
[Unprotonated Form]
or pH = pK a +log
[Protonated Form]
Therefore, if 70% of this functional group is ionized:
[30]
pH = 8.2 + log
[70]
[30] Page2of2
pH = 8.2 + log = 8.2 + ( −0.37) = 7.83
[70]
Because a pH=7.83 does not exist physiologically, this percent ionization could only occur in an
exogenously prepared solution.
2.4 Salts and Solubility
1. Some drug molecules can be formulated as either a potassium salt or hydrochloride salt. Evaluate all of
the acidic and basic functional groups in each of the drug molecules drawn below and fill in the grid with
the appropriate information.
Answer
Name of Functional Name of Functional Is the Hydrochloride

Name of Drug Group That Can Form Is the Potassium Salt Group That Can Form a Salt Acidic, Basic, or
Molecule a Potassium Salt Acidic, Basic, or Neutral? Hydrochloride Salt Neutral?
Arformoterol Phenol Basic Secondary amine Acidic
Baclofen Carboxylic acid Basic Primary amine Acidic
Irbesartan Tetrazole Basic Amidine Acidic
Ciprofloxacin Carboxylic acid Basic Secondary amine (NH) Acidic
component of piperazine
Aniline component (N) of Acidic

piperazine
Tetracycline Phenol Basic Tertiary amine Acidic
2. Each of these drug molecules will treat a particular ailment by either managing a symptom or
β-dicarbonyl Basic
modulating
Note: The ionized aform
biochemical pathway.
of an acidic In either
functional case,
group the drugthe
is termed hasconjugate
to get to its biological
base of that target. Using your
functional
group. The ionized form of a basic functional group is termed the conjugate acid of that functional group.
knowledge about functional group character, describe how both of the drugs get to their respective
biological targets. Consider the concepts of solubility, absorption, distribution, and route of administration
2. Each of these drug molecules will treat a particular ailment by either managing a symptom or modulating
a biochemical pathway. In either case, the drug has to get to its biological target. Using your knowl-
in your answer. [pH (stomach) = 1; pH (intestine) = 8; pH (plasma) = 7.4]
edge about functional group character, describe how both of the drugs get to their respective biological
targets. Consider the concepts of solubility, absorption, distribution, and route of administration in your
answer. [pH (stomach)=1; pH (intestine)=8; pH (plasma)=7.4]
Cl NCH3
OH
O
O
N CH2OH
O
CONH2
Scopolamine
Loperamide

3. Based on your structural evaluation, provide a rationale for why each of these drugs cannot be
109
delivered via an oral route of administration, or why there is limited absorption of the drug when it is
Biological Targets and Routes of Administration

Loperamide: µ opioid receptors located in the large intestine; oral administration
Scopolamine: muscarinic acetylcholine receptors (M1) located in the peripheral nervous system;
transdermal administration
Answer
Loperamide:
• Oral tablet is swallowed.
• Tablet dissolves in aqueous contents of the stomach (requires drug to be water soluble).
The amide, piperidine (tertiary amine), and tertiary alcohol have hydrophilic character and
contribute to the water solubility of the drug.
• Do not want absorption into systemic circulation via stomach lining.
The piperidine (tertiary amine pKa=9–11) will be predominantly ionized in the stomach
pH=1 (pH < pKa).
• Distribution into intestine—smaller fraction in ionized form; retain water solubility.
The piperidine (tertiary amine pKa=9–11) will be somewhat less (but still predominantly) ionized
in the intestine pH=8 (pH < pKa).
• Interaction with receptor located in intestine—there is no need for absorption out of the gastro-
intestinal (GI) system and into systemic distribution.
Scopolamine:
• Patch is placed on skin.
• Absorption of drug occurs from patch into skin lipophilic bilayer (requires hydrophobic
character).
The aromatic ring and bicyclic heterocycle contribute to hydrophobic character of the drug and
allow for absorption and transport through skin.
• Drug transports through skin and dissolves into circulation (requires drug to be water soluble).
The bicyclic heterocycle (tertiary amine pKa=9–11) will be primarily ionized in the plasma pH=7.4
(pH < pKa). The ester, ether, and primary alcohol are hydrophilic in character and contribute to
the water solubility of the drug.
• Distribution to peripheral receptors (requires drug to be water soluble).
The bicyclic heterocycle (tertiary amine pKa=9–11) will be primarily ionized in the plasma pH=7.4
(pH < pKa). The ester, ether, and primary alcohol are hydrophilic in character and contribute to
the water solubility of the drug.
• Interaction occurs with receptors located in periphery.
OH
O
O
N CH2OH 2.4 Salts and Solubility 111
O
CONH2
3. Based on your structural evaluation, provide a rationale for why each of these drugs cannot be deliv-
Scopolamine
ered via an oral route of administration, or why there is limited absorption of the drug when it is
Loperamide
Insulin Structure
ased on your structural evaluation, provide aS rationale for why Seach of these drugs cannot be A Chain
H2NofGly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn COOH
ered via an oral route administration, or why there is limited absorption of the drug when it is
S S
nistered orally. S S B chain
H2 N Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg
Gly
HOOC Thr30 Lys29 Pro28 Thr27 Tyr Phe Phe

PO3Na2
H2N PO3Na2
OH
Alendronate
Insulin Answer
Insulin is a molecule composed of two peptide subunits connected to one another via two disulfide
linkages. Peptide bonds do not survive the hydrolytic environment found in the stomach. Insulin can
undergo acid catalyzed hydrolysis in the aqueous environment of the stomach, as well as enzymati-
cally catalyzed hydrolysis in the same physiological compartment. Because of this rapid degradation,
peptide-based drugs like insulin cannot be delivered via the oral route.
Alendronate contains two ionizable phosphonates, an ionizable primary amine, and a tertiary
alcohol. These functional groups impart significant hydrophilic character and make alendronate very
water soluble. There is very, very, little hydrophobic character to contribute to absorption across the
GI mucosal membranes. Although alendronate can be administered orally, less than 6% of a given
dose is absorbed and distributed systemically.
Embeconazole
Answer
Can this be formulated as

a. a topical ointment or cream? YES NO
b. an aqueous solution? YES NO
c. Which structural features and corresponding characteristics did you consider when answering
each of these questions?
Although there are hydrophilic functional groups that can participate in hydrogen bonding
interactions with water and impart a reasonable amount of water solubility (fluorine atoms on
the aromatic hydrocarbons, tertiary alcohol, a weakly basic nitrogen containing heterocycle [1,2,4
triazole], and oxygen containing heterocycle [1,3 dioxane]), their effect is overwhelmed by the
functional groups that are hydrophobic in character (two aromatic hydrocarbons, alkene, thio-
ether). This hydrophobic character allows for good drug penetration into and across the skin if
applied as a topical cream or ointment; however, this character is likely to significantly limit the
drug’s water solubility as an aqueous solution.

2.5Section 3 General Self Assessment Answers
Drug Binding Interactions
1. Both delapril and lisinopril are inhibitors of angiotensin converting enzyme (biological target) a
2.5
2.5 Drug Binding Interactions

other interacts with a Zn+2 atom. Both of these interactions are critical for drug action. Do the followin
Drug Binding Interactions
a. Modify the molecules below to show the form of the active drug at physiological pH.
1. Both delapril and lisinopril are inhibitors of angiotensin converting enzyme (biological target) a
b. Identify the type of interaction possible between the carboxylic acids and the residues pr
other interacts with a Zn+2 atom. Both of these interactions are critical for drug action. Do the followin
1. Both delapril and lisinoprila.arewithin

Modify
the biological
inhibitors target. converting enzyme (biological target) and as such
of angiotensin
the molecules below to show the form of the active drug at physiological pH.
are valuable drugs used in the management of hypertension. The active form of these drugs requires the
Answer:
presence of two carboxylic acids or twothefunctional groups thatpossible
can participate
b. Identify type of interaction betweeninthe
similar types of
carboxylic interactions
acids and the residues pr
at physiological pH. One of the carboxylic acids interacts with an active site arginine residue, and the other
interacts with a Zn+2 atom. Both within the biological
of these target.
interactions are critical for drug action. Do the following:
a. Modify the molecules below to show the form of the active drug at physiological pH (pH=7.4).
Answer:
b. Identify the type of interaction possible between the carboxylic
H 2N
acids and the residues present within
the biological target. Zn
2+ CH2 R
O + N
Answer NH2
– – H
O O C H3 O
+ H 2N
2+ N CH2 R
Zn N O + N
H H O NH2
– – H
O O C H3 O
+
Delapril N
N
H H O
Ionic interactions areDelapril

possible between the carboxylic acids and the zinc ion and the ionized arginine

residue.
Ionic interactions are possible between the carboxylic acids and the zinc ion and the ionized arginine
residue.
Ionic interactions are possible between the carboxylic acids and the zinc ion and the ionized arginine
residue.
Lisinopril
Lisinopril
113
2.used in the treatment
Tolterodine of overactive
(Detrol®), fesoterodine bladder.
(Toviaz® Based
), and on the structure
oxybutynin (Ditropan®evaluation process described
) are anticholinergic agents in
Chapter 6* and previous chapters,* “read” each of these drug molecules and determine how each
of these drug molecules interact via hydrogen bonding with the muscarinic receptor. Fill in the grid
provided with your answers.
Tolterodine Fesoterodine
Oxybutynin
Answer
Function Function
H-bond donor, One amino acid that interacts (via side
Name of H-bond chain) with the functional group via a
Functional Name of ALL Anticholinergics That acceptor, both complementary H-bonding interaction;
Group Contain Functional Group or neither NONE is a possible answer
Alkane (i.e., Tolterodine, fesoterodine, oxybutynin Neither None
alkyl chain)
Cycloalkane Oxybutynin Neither None
Aromatic hydro- Tolterodine, fesoterodine, oxybutynin Neither None
carbon
Alkyne Oxybutynin Neither None

Tertiary alcohol Oxybutynin Both Serine, threonine, cysteine, tyrosine, glutamic
acid, aspartic acid, lysine, arginine, asparagine,
glutamine, histidine, tryptophan
Primary alcohol Fesoterodine Both Serine, threonine, cysteine, tyrosine, glutamic
2.5 Drug Binding Interactions 115
Continued from previous page

Phenol Tolterodine Both Serine, threonine, cysteine, tyrosine, glutamic
Tertiary amine Oxybutynin, fesoterodine, tolterodine Acceptor Serine, threonine, cysteine, tyrosine, glutamic
Ester Fesoterodine, oxybutynin Acceptor Serine, threonine, cysteine, tyrosine, glutamic
Note: Please remember that if a functional group is ionized, then it can no longer participate in
hydrogen bonding interactions.
3. Each of the three odorant molecules drawn below produces a unique scent on interaction with the
olfactory receptors. Unlike most biological targets for drug action, olfactory receptors typically have
anEach
3. affinity
of for
the athree
wideodorant
variety molecules
of odorantdrawn
molecules
belowand can adopt
produces uniquescent
a unique conformations to enhance
on interaction with the
the affinity of a given odorant for the receptor. Based on the structural features found in each mole-
cule, what
olfactory type of Unlike
receptors. interactions are possible
most biological withforthe
targets olfactory
drug receptorsreceptors
action, olfactory at physiological
typically pH?
haveIndicate
an
which functional group(s) can participate in each of the interactions identified.
Sclareol Nerolidol
(herbal scent) Vanillin (green
(greenwoody
woodyscent)
scent)
Sclareol Vanillin Nerolidol

Interaction Type Functional Group Interaction Type Functional Group Interaction Type Functional Group
4.Hydrophobic Cycloalkane,
There are five basic aliphatic
flavors van der
that our Waals,
taste Phenol
receptors detect: salty, van der Waals,
sour, Aliphatic
sweet, bitter, andalkanes
umami
alkane, alkene Hydrophobic Hydrophobic and alkenes
(savory). The taste Tertiary
Hydrogen bond receptors are located
alcohol on taste
Hydrogen bondbuds that areether,
Phenol, on our tongue, soft
Hydrogen palate, Tertiary
bond epiglottis, and
alcohol
(acceptor and donor) (acceptor) aldehyde (acceptor and
donor)
Ion–dipole Tertiary alcohol Hydrogen bond Phenol
(as the dipole) CO2 H (donor)
Ion–dipole Phenol, ether,
(as the dipole) aldehyde
H 2N CO2 H
N H
N
Sclareol Nerolidol
116 Medicinal scent)
(herbal Assessment Vanillin
Chemistry Self (green woody scent)
4. There are five basic flavors that our taste receptors detect: salty, sour, sweet, bitter, and umami
(savory). The taste receptors are located on taste buds that are on our tongue, soft palate, epiglottis,
and
4. upper
There esophagus.
are five basicSour andthat
flavors saltyour
flavors
tasteare mediated
receptors by ion
detect: channels,
salty, whereas
sour, sweet, sweet,
bitter, bitter,
and umami
and umami flavors are derived from activation of the respective G-protein coupled receptor. The
(savory). The taste
umami receptor is receptors
activatedare located on
by L-amino tastespecifically
acids, buds that are on our tongue,
glutamate. soft palate,
Determine epiglottis, and
what interactions
are possible with the side chain of glutamate (at physiological pH) and then determine if any of the
following flavor molecules can interact with and activate this receptor.
CO2 H
H 2N CO2 H
N H
N
O
HO P N N
HO O O
OH
HO
Shitaki Mushrooms
Inosinic Acid
Answer
The side chain of glutamic acid (glutamate) contains a carboxylic acid that will be ionized at physiological
pH. In its ionized form glutamic acid can participate in an ionic interaction or in an ion–dipole inter-
action (as the ion). The functional groups in both cucumber and green pepper flavor cannot partici-
pate in ionic interactions with glutamate as none of the functional groups are ionized (cationic) at
physiological pH. Ion–dipole interactions (as the dipole) are possible between glutamate and the
aldehyde found in cucumber flavor and the methyl ether found in green pepper flavor. Inosinic acid is
a component found with shitaki mushrooms that is thought to contribute to their unique flavor. Struc-
tural evaluation of this molecule reveals a phosphate that is ionized at physiological pH. This functional
group can participate in ion–dipole interactions with the umami receptor to elicit a savory flavor.

2.6 Stereochemistry and Drug Action

2.6
Stereochemistry and Drug Action
compounds,
compounds, identify
identify allcenters.
all chiral chiral centers.
N OH
O O
OH
HN HO
Estradiol
O
Acebutolol
H
H3C N C H3
O
S H3 CO2 C CO2 CH3
N C H3
H NO2
OH N S N
O N
CO2 H N N
Cefamandole Nifedipine
117
Answer:
Answer
OH
N
O O * * *
OH
*
* *
HO
HN
Estradiol
5 chiral centers
O
Acebutolol
1 chiral center H
H3C N C H3
O
S H3 CO2 C CO2 CH3
* N * * C H3
NO2
H
OH N S N
O N
CO2 H N N
Nifedipine
Cefamandole 0 chiral centers
3 chiral centers The highlighted carbon atom
is symmetrical
3. Shown below is the structure of fluvastatin, an HMG-CoA reductase inhibitor used to lower plasma LDL levels.
2. For each of the four drug molecules shown in question 1:
Fluvastatin contains two chiral centers, designated as A and B. Using the structure of fluvastatin and the Cahn-
a. Identify if it can have an enantiomer. Provide an explanation for your response.
Ingold-Prelog (CIP) if
b. Identify system,
it can determine the R/S configurations
have a diastereomer. Provide anfor each of its for
explanation chiral centers.
your response.
c. Identify if it can have a geometric isomer. Provide an explanation for your response.
Answer HO A
CO2 H
a. Acebutolol, estradiol, and cefamandole can have enantiomers, while nifedipine cannot. For a
drug molecule to have an enantiomer, its structure must
B OH contain at least one chiral center. Acebu-
tolol, estradiol, and cefamandole all meet this criterion. Because the structure of nifedipine does
H
not contain a chiral center, it cannot have enantiomers.
b. Estradiol and cefamandole can have diastereomers, but acebutolol and nifedipine cannot. For
F
a drug molecule to have a diastereomer, its structure must contain at least two chiral centers.
Because the structures of estradiol and cefamandoleN have five and three chiral centers, respec-
tively, these two drug molecules meet this criterion and can have diastereomers. Acebutolol (one
chiral center) and nifedipine (0 chiral centers) do not meet this criterion and thus cannot have
diastereomers.
c. Estradiol and cefamandole can have geometric isomers, while acebutolol and nifedipine cannot.
Geometric isomers are a specialized type ofFluvastatin
diastereomer and result from restricted rotation
about a carbon–carbon bond. Geometric isomers can occur in the presence of either a double
bond or an alicyclic ring. Both estradiol and cefamandole contain alicyclic rings and thus can
have geometric isomers. Acebutolol and nifedipine do not meet the above criterion and cannot
Page2of3

2.6 Stereochemistry and Drug Action 119
have geometric isomers. Please note that the double bonds seen in the 1,4-dihydropyridine ring
of nifedipine reside in a six-membered ring and thus cannot participate in the formation of
geometric isomers.

3. Shown below is the structure of fluvastatin, an HMG-CoA reductase inhibitor Chapters
used1.6
to and
lower2.6plasma
LDL levels. Fluvastatin contains two chiral centers, designated as 1 and 2. Using the structure of
Revised(CIP)
fluvastatin and the Cahn-Ingold-Prelog structure reflects
system, chiral carbons
determine the R/S #1 and #2.
configurations for each of its
chiral centers.
HO 1
CO2 H
2 OH
H
C H3
F
N
C H3
Fluvastatin
Answer:
Answer
D
A
C
Chiral center 1 Chiral center 2 A

B B
D
C
Fluvastatin Fluvastatin
Using the CIP sequence rules for chiral center 1, the hydroxyl group (A) has the first priority because
oxygen always has priority over carbon. Carbon atoms B and C are identical because each is attached
4. Shown below is the enantiomer of fluvastatin. Which of the following properties/actions would be expected to
to one carbon atom and two hydrogen atoms. It is therefore necessary to examine the two adjacent
carbon for
be identical atoms. The carbon
fluvastatin and itsatom adjacent
enantiomer andtowhich
carbon C (O,O,O)
would has priority
be expected over the carbon atom adja-
to be different?
cent to carbon B (O,C,H); thus, the final priority is hydroxyl group (A) > carbon atom C > carbon atom
B > a.
hydrogen
Percentatom (D). The
ionization at ahydrogen
pH of 7.4 atom is projected into the paper and located away from the
reader. Applying the above priorities reveals a clockwise orientation. Thus, the correct designation
for chiral center 1 is R.
Using the CIP sequence rules for chiral center 2, the hydroxyl group (A) once again has the first
priority, and the hydrogen atom (D) has the leastH Opriority. Carbon atom C (C,C,H) has priority over
CO2 H
carbon atom B (C,H,H); thus, the final priority is hydroxyl group (A) > carbon atom C > carbon atom
OH
H
B > hydrogen atom (D). Unlike chiral center 1, the hydrogen atom of chiral center 2 is projected out
of the paper and located directly toward the reader. In situations like this, there are three options:
Answer:
(1) redraw the chiral center with the hydrogen projected into the paper while maintaining the
correct stereochemical orientation of all other groups;
(2) imagine that you are viewing the object from the other side of the paper; or
D
(3) use the given projection
A
C
and make an alteration in your final answer.
Options 1 and 2 are often difficult for students to accomplish without producing errors; therefore,
optionChiral center 1 Initially “pretend” that the hydrogen
3 is suggested. Chiral center
atom (or2the atom ofA lowest priority) IS
projected into the plane ofBthe paper and apply the sequence rules. In this Bcase, there is a clockwise
orientation that is consistent with the R isomer. Because it was necessary to invert the D stereochem-
istry of the chiral center to do this, the correct designation is the exact opposite. CIn this case, chiral
center 1 has the S configuration.
4. Shown below is the enantiomer of fluvastatin. Which of the following properties/actions would
be expected to be identical for fluvastatin and its enantiomer and which would be expected to be
different?
Fluvastatin Fluvastatin
a. Hepatic metabolism
b. Water solubility
4. Shown
c. below is the
Adverse enantiomer
effect profile of fluvastatin. Which of the following properties/actions would be expected to
d. Active
be identical renal reabsorption
for fluvastatin by transport
and its enantiomer proteins
and which would be expected to be different?
e. Potency (dosage given)
a. Percent ionization at a pH of 7.4
f. Percent ionization at a pH=7.4
HO
CO2 H
OH
H
F
N
Enantiomer of
Fluvastatin
Answer
Enantiomers have identical physical and chemical properties, with the exception of the direction
in which they rotate plane polarized light. Thus, water solubility and the percent ionization of the
carboxylic acid at a pH of 7.4 would be expected to be identical. The major difference and most
important aspect of enantiomers are their relative abilities to interact with three-dimensional
biological targets. Hepatic metabolism and active renal reabsorption depend on binding to metabo-
lizing enzymes and transport proteins, respectively, and would be expected to be different. Adverse
effects can be due to the interaction of these drug molecules with other biological targets and/or the
2.6 Stereochemistry and Drug Action 121
formation of a specific metabolite. Differences in potency can result in differential metabolism (i.e.,
one enantiomer may be inactivated quicker than the other) or differential binding to the biological
target.

Note: References to chapters are related to Chapter 7 in Harrold MW and Zavod RM, Basic Concepts in Medic-
inal Chemistry, American Society of Health-System Pharmacists, ©2013.
2.7 Drug Metabolism
2.7
Drug is
1. Heroin Metabolism
a synthetic derivative of the naturally occurring opioid analgesic morphine. Given its illicit
nature, heroin is not subject to Food and Drug Administration (FDA) regulation; therefore, the actual
1. Heroin isofaasynthetic
composition derivative
given heroin batchof the naturally
varies occurring
significantly. opioidmolecules
The three analgesicdrawn
morphine.
belowGiven its illicit
represent the
three major components found within a batch of heroin. The users’ intense rush has been attributed to
morphine. Which phase I transformation is responsible for the conversion of heroin to morphine?
the conversion of heroin into morphine. Which phase I transformation is responsible for the conversion of
heroin to morphine?
Heroin Morphine
2. Estradiol, the estrogen component of many oral contraceptives, undergoes a phase II conjugation then
Answer
Heroin is the diacetyl ester of morphine. Two successive phase I ester hydrolysis reactions are responsible
forreabsorbed (at least
the conversion in part).to
of heroin Consider the structure of estradiol drawn below and do the following:
morphine.
transformation).
2. Estradiol, the estrogen component of many oral contraceptives, undergoes a phase II conjugation reaction
to produce b.aWhich
metabolite
enzyme that is eliminated
is required viathis
to make a fecal route
sulfate (at least in part). The conjugated hormone
conjugate?
undergoes a process called enterohepatic recycling. In this process the sulfate conjugate is cleaved by gut
bacteria toAnswer: Sulfotransferase
regenerate the active drug,(SULT)
which is then reabsorbed (at least in part). Consider the structure
of estradiol drawn below and do the following:
transformation).
b. Which enzyme is required to make this sulfate conjugate?
Answer: Sulfatase
Answer
Sulfotransferase (SULT)
-
123
transformation).
b. Which enzyme is required to make this sulfate conjugate?
Answer: Sulfotransferase (SULT)

c. Which deconjugating enzyme catalyzes removal of the sulfate group thus allowing for entero-
hepatic recycling?
Answer
Sulfatase
Answer: Sulfatase
-

3. Metabolites do not necessarily have the same mechanism of action as the parent drug. In the case of
chlorimipramine (a tricyclic antidepressant that inhibits serotonin uptake), a phase I transformation
produces a metabolite that is also a tricyclic antidepressant, but whose mechanism of action is via
inhibition of norepinephrine reuptake. Which phase I transformation has occurred? What additional
phase I transformations
3. Metabolites are possible?
do not. In the case of I transformations are possible?
Chlorimipramine
Answer
4. Evaluate each of the which phase I metabolic transformation has occurred.
Phase I transformation that has occurred: oxidative N-dealkylation
Other phase I transformationsHpossible: ortho/para aromatic hydroxylation; benzylic oxidation;
N-oxidation; oxidative N-dealkylation
N C H(there is still a methyl group); oxidative deamination (of the
3 N H2
doubly-demethylated product). One of the products from the oxidative deamination is an aldehyde,
which can undergo further oxidation (aldehyde oxidation) to the carboxylic acid.
C H3 C H3
CF3 CF3
Dexfenfluramine

2.7 Drug Metabolism 125
Chlorimipramine
4. Evaluate each of the following metabolic transformations and determine which phase I metabolic
transformation has occurred.
4. Evaluate each of the which phase I metabolic transformation has occurred.
H
N C H3 N H2
C H3 C H3
CF3 CF3
Dexfenfluramine
Fluvoxamine
H2N CO2 H O
O
OH OH
Cl Cl
Baclofen
Answers
Oxidative N-dealkylation
Oxidative O-dealkylation
Oxidative deamination followed by oxidation of the resulting aldehyde to a carboxylic acid

Note: References to chapters are related to Chapter 8 in Harrold MW and Zavod RM, Basic Concepts in Medic-
inal Chemistry, American Society of Health-System Pharmacists, ©2013.
Part 2 ANSWERS
Section 4 – Whole Molecule Drug

Evaluation
2.8 Aliskiren..................................................................... 129
2.9 Aripiprazole................................................................ 137
2.10 Cefprozil..................................................................... 143
2.11 Cetirizine.................................................................... 149
2.12 Chlorpropamide and Other Sulfonylureas.................. 153
2.13 Dabigatran Etexilate.................................................. 159
2.14 Fenofibrate and Gemfibrozil....................................... 165
2.15 Fluvoxamine............................................................... 169
2.16 Haloperidol................................................................ 173
2.17 Hydrocortisone........................................................... 177
2.18 Levothyroxine (T4)...................................................... 183
2.19 Lidocaine.................................................................... 189
2.20 Montelukast and Zafirlukast...................................... 193
2.21 Phenobarbital and Other Barbiturates....................... 199

2.22 Pravastatin and Fluvastatin........................................ 205
2.23 Quinapril.................................................................... 211
2.24 Rivastigmine.............................................................. 217
2.25 Sitagliptin................................................................... 223
2.26 Sorafenib.................................................................... 227
2.27 Zanamivir and Oseltamivir......................................... 233
Answers
2.8 Aliskiren
Aliskiren is an orally active agent used in the treatment of hypertension. This non-peptide drug acts as an inhibitor
of renin, the enzyme that converts angiotensinogen (its endogenous substrate) to angiotensin I. Biologically inactive,
angiotensin I is rapidly converted to angiotensin II by angiotensin converting enzyme. Angiotensin II is a potent
agonist when bound to its receptor and produces significant vasoconstriction, as well as an increase in blood pressure.
In the presence of aliskiren, angiotensinogen is not converted to angiotensin I so less angiotensin II is produced to
activate the angiotensin II receptor. Consequently less vasoconstriction occurs, and a drop in blood pressure results.
1. Conduct a structural evaluation of aliskiren, focusing on the boxed functional groups and use the informa-
Chapter 1.8/2.8 (remove bold from drug name x2)
tion in the grid to inform your answers to the questions that follow.
E
D F
A
B
Aliskiren
C
Aliskiren
129
Answer
Function
Amino Acids That
Function Can Interact with
Character
Interaction(s) the Functional
Character Acidic, Basic, or Function Group via Ion–
Possible with
Neutral ↑ Solubility Dipole Interactions
Name of Hydrophilic Biological Target
Functional and/or Provide pKa and/or at Physiological at pH=7.4
A Ether Hydrophilic (O) Neutral Solubility (O) H-bonding (A) Asp, Glu, Lys, Arg
Hydrophobic (R) Absorption (R) Dipole–dipole
Ion–dipole (as the
dipole)
B Aromatic hydro- Hydrophobic Neutral Absorption Hydrophobic None
carbon van der Waals
π-π stacking
C Aliphatic alkane Hydrophobic Neutral Absorption Hydrophobic None
van der Waals
D Primary amine Hydrophilic (NH2) Basic Solubility (NH2) Ion–dipole (as the ion) Ser, Thr, Cys, Tyr, Asn,
Hydrophobic (R) pKa ~9–11 Absorption (R) Ionic Glu, His, Trp
Chapter 1.8/2.8 (remove bold from drug name x2)
E Secondary alcohol Hydrophilic (OH) Neutral Solubility (OH) H-bonding (A + D) Asp, Glu, Lys, Arg
E Ion–dipole (as the
D dipole)
F
F Amide Hydrophilic A Neutral Solubility H-bonding (A) Asp, Glu, Lys, Arg
(CONH2) (CONH2) Dipole–dipole
B
Hydrophobic (R) Absorption (R) Ion–dipole (as the
dipole)
Aliskiren
2. Aliskiren is marketed as the pure 2S, 4S, 5S, 7S
C enantiomer. Circle all of the chiral carbon atoms and
determine if diastereomeric or geometric isomers are possible.
Aliskiren
2.8 Aliskiren 131
Answer (remove bold from drug name) Chapter 2.8
Aliskiren
If there are two or more chiral carbon atoms, then it is possible for the drug to have diastereomeric
forms. In the case of aliskiren,
(remove boldthere
from are
drugfour chiral
name) carbon
Chapter atoms; therefore, there are a lot of poten-
1.8/2.8
tial diastereomeric forms. A quick reminder on how to determine if a pair of isomers is diastereo-
meric—if one chiral carbon is held constant (e.g., R-isomer) and you vary at least one additional chiral
carbon, then the pair of isomers will be diastereomeric to one another. In the example shown below,
the chiral center Ifthat
there areheldisconstant
is circled and theand
held constant (*) chiral
the (*)center
chiraliscenter
varied.isThe pair of
varied. Theisomers
pair ofdrawn are diastereom
isomers
drawn are diastereomers.
*
Amlodipine
For geometric isomers to be possible there must be restricted rotation around a carbon–carbon
bond (e.g., presence 4.
of aApproximately
double bond 25% of the ring).
or alicyclic absorbed dose ofofaliskiren
Evaluation aliskirenis reveals
excreted
theinabsence
the urineofunchanged.
double bonds and alicyclic rings; therefore, geometric isomers cannot exist.
transformation has occurred and whether or not it represents an oxidative transformation.
A
*
3. Although aliskiren is administered orally, its oral bioavailability is ~2.5% and is very poorly absorbed.
Using the information in the structure evaluation grid, provide a structural rationale for this unfortu-
nate property.
Answer
Oral bioavailability is dependent on the drug’s ability to dissolve in the aqueous contents of the
gastrointestinal (GI) tract and its ability to cross the lipid bilayer membrane. The hydrophilic char-
acter of the drug promotes aqueous solubility. Evaluation of the entire molecule (not just the boxed
functional groups) for hydrophilic character reveals two ethers, two amides, a primary amine (in its
ionized form), and a secondary alcohol that will contribute meaningfully to the hydrophilic character
of the drug. (NOTE: the drug is sold as a hemifumarate salt that further increases the overall water
solubility of the drug.) The hydrophobic character* of the drug promotes absorption across the lipid
bilayer. Evaluation of the entire molecule (not just the boxed functional groups) for hydrophobic
character reveals an aromatic hydrocarbon, a lipophilic ether, and several aliphatic alkanes. The drug
is formulated as a water soluble salt and had ample hydrophilic character. Unfortunately it does not
have sufficient hydrophobic character to allow for meaningful absorption.
4. Approximately 25% of the absorbed dose of aliskiren is excreted in the urine unchanged. It is
unknown how much 4. Approximately
of an 25%
absorbed dose of the absorbed
is metabolized, anddose of aliskiren
several is excreted
metabolites in the urine unchanged. It is
from CYP3A4
mediated transformations have been identified. Several possible metabolic products are illustrated.
transformation has occurred and whether or not it represents an oxidative transformation.
Identify which metabolic transformation has occurred and whether or not it represents an oxidative
transformation.
B
2.8 Aliskiren 133
Answer
5. Renin catalyzes the cleavage of a specific Leu-Val peptide bond within the structure o
Name of Metabolic Transformation Oxidative or Non-Oxidative
A Oxidative O-dealkylationchains of these two amino acids and box the non-hydrolyzable hydroxyethylene group.
Oxidative
B Alcohol oxidation Oxidative
C Oxidative deamination Oxidative
D Oxidative O-dealkylation* Oxidative
E Amide hydrolysis* Non-oxidative
* This metabolite has been identified as one of the two primary metabolites produced.
5. Renin catalyzes the cleavage of a specific Leu-Val peptide bond within the structure of angiotensin-
5. The
ogen. Renin catalyzes
structure the cleavage
of aliskiren of afunctional
contains specific Leu-Val
groupspeptide bondthe
that mimic within
side the structure
chains of side
for these two
amino acids. The hydrolyzable peptide bond (found between Leu-Val) has been replaced by a non-
chains of
hydrolyzable these two aminogroup
hydroxyethylene acids in
and box the non-hydrolyzable
aliskiren. hydroxyethylene
Circle the functional groups that group.
mimic the amino
acid side chains of these two amino acids and box the non-hydrolyzable hydroxyethylene group.
Answer:
Answer
H3 C C H3
H3C
HO H H3C C H3
H2 N N N H2
(remove bold from drug name) Chapter 2.8
O O O
H3 CO H3C C H3
6. Aliskiren can be co-administered with other anti-hypertensive agents to provide better likely is it
6. Aliskiren can be co-administered with other anti-hypertensive agents to provide better hypertension
Aliskiren
that a plasma
management. protein is
Amlodipine binding interaction will occur
a second-generation if these drugscalcium
dihydropyridine are co-administered?
channel blocker used in
the treatment of hypertension. Aliskiren and amlodipine are both plasma protein bound (47–51%
and 93–97%, respectively). How likely is it that a plasma protein binding interaction will occur if
these drugs are co-administered?(remove bold from drug name) Chapter 1.8/2.8
Amlodipine
Amlodipine
2.8 Aliskiren 135
Answer
It is important to first determine whether these drugs are basic, acidic, or amphoteric in nature.
Based on a structural evaluation of the entire aliskiren molecule (not just the boxed functional
groups), there is one basic functional group (primary amine) and no acidic functional groups present.
The same evaluation for amlodipine yields identification of two basic functional groups (primary
amine and dihydropyridine ring) and no acidic functional groups. Based on this evaluation, both
drugs are basic and both would be bound to α1-acid glycoprotein (plasma protein). It is important to
remember that plasma protein binding interactions are likely to happen when a drug is >90% plasma
protein bound. Given the extent to which amlodipine is plasma protein bound, it is highly likely that
a plasma protein binding interaction will occur when aliskiren displaces amlodipine from the glyco-
protein binding site. When this type of interaction occurs, there will be a greater fraction of amlo-
dipine present in its unbound form. This leads to an increase in pharmacological activity resulting in
hypotension (excessively low blood pressure).

Answers
2.9 Aripiprazole
2.9
2.9Aripiprazole
Aripiprazole
Shown below is the structure of aripiprazole, a serotonin receptor modulator used for the treatment of depression,
Shown
Shownbelow
belowisisthe
theor
orused
usedfor
for the
the treatment ofof depression,
depression,schizophrenia,
schizophrenia,autism,
autism, mania,
mania, and
and bipolar
bipolar disorder.
disorder.
schizophrenia, autism, mania, and bipolar disorder.
Aripiprazole
Aripiprazole
1. Identify all ofall

1. Identify theofacidic
wouldand
be basic functional
primarily ionizedgroups, provide at
or unionized thea normal
urine pHpKofa range
5.6. for each of the identi-
1.
fiedIdentify all groups,
functional of wouldand
beidentify
primarily ionized
if each or unionized
functional at a urine
group would pH of 5.6.
be primarily ionized or unionized at a
urineAnswer
pH=5.6.
Answer
Answer
Tertiary amine (Basic functional group)
Tertiary amine (Basic O
Normal pH range = 9 tofunctional
11 group) H
NH O
Normal
Would be pHprimarily
range =ionized
9 to 11at a pH = 5.6
Would be primarily ionized at a pH = 5.6 N
Cl Cl O
Cl Cl O
N N
N N Aripiprazole
Aripiprazole
Aromatic amine (Aniline, Basic functional group)
Normal pH
Aromatic range(Aniline,
amine = 2 to 5 Basic functional group)
Would be primarily unionized at a pH = 5.6
Normal pH range = 2 to 5
Would be primarily unionized at a pH = 5.6
2. Identify all of the of aripiprazole.
Answer
2. Identify all of the of aripiprazole.
3. Answer
3. Alkyl (aliphatic) chain

(Lipid soluble)
Alkyl (aliphatic)
137 chain
Ether oxygen
Halogens (Lipid soluble) Amide
(Water soluble) O (Water soluble)
2. Replacementstructurefortheanswertoquestion2inChapter2.9(Aripiprazole)
Identify all of the remaining functional groups, and indicate how each group contributes to the
overall water solubility or the overall lipid solubility of aripiprazole.
Answer

(Lipid soluble)
Ether oxygen
Halogens (Water soluble) Amide
(Lipid soluble) (Water soluble)
Hydrocarbon portion
of bicyclic ring
(Lipid soluble)
Aromatic (phenyl) ring
(Lipid soluble)
Aripiprazole

(Lipid soluble)
3. Using your answers from the previous two questions, provide an explanation as to why aripiprazole
can be administered orally for the indications previously listed.
Sulfonylureas)
Answer
The tertiary amine, aromatic amine, amide, and ether oxygen atom provide adequate water solu-
bility that allows aripiprazole to dissolve in the aqueous contents of the gastrointestinal (GI) tract.
Once dissolved, aripiprazole must pass through the GI mucosal membrane to enter the blood stream.
The dichloro phenyl ring, the alkyl chain, and the hydrocarbon portion of the bicyclic ring will
provide adequate lipid Cl solubility to allow for absorption across
O the mucosal membrane. The tertiary
amine will be primarily ionized within O O
the GI tract, whereas the aromatic amine will be primarily
unionized once it leaves the stomach. Remember thatSionization N N is an equilibrium process with some
fraction of unionized molecules present at all times. AccordingH H Le Chatelier’s principle, as soon as
to
N O
one unionized molecule passes through H the GI membrane, the equilibrium will reset to provide addi-
tional unionized molecules. O This same principle also allows ionizable functional groups to penetrate
the blood–brain barrier Hand 3 C enter the central
Glyburide
nervous system (CNS). The same functional groups that
allowed aripiprazole to pass through the GI mucosal membrane will also provide sufficient lipid solu-
bility to allow it to cross the blood–brain barrier and reach its target receptors within the CNS.
O OH
O O
H3C S N N
H H
N O
H
2.9 Aripiprazole 139
4. Using your answers from the previous
4. Drug molecules that are highly plasma protein bound may undergo a drug interaction due to the
5. Drug molecules
displacement or losartan?
of one drug molecule from a plasma protein by another drug molecule. Shown below
are the structures of tolbutamide and losartan. Both of these drugs are highly plasma protein bound.
Aripiprazole is also highly plasma protein bound (>99%). Would you expect there to be a drug inter-
action between aripiprazole and either tolbutamide or losartan?
4. Using your answers from the previous

Tolbutamide
5. Drug molecules or losartan?

Losartan
Answer
The6.answer
Assumeherethat thisTolbutamide
is no. that this binding
andinteraction occurs
losartan are at adrug
acidic physiological
moleculespH of to
due 7.4.the presence of
an acidic sulfonylurea and a tetrazole functional group, respectively. Aripiprazole is a basic drug
molecule due to the presence of a tertiary amine and an aromatic amine. Acidic drug molecules
primarily bind to albumin, whereas basic drug molecules primarily bind to α1-glycoprotein. Plasma
protein binding interactions (also known as plasma protein displacement D interactions) occur due to
the nonspecific nature of the plasma proteins that bind and transport drug molecules. These types of
A
interactions are only therapeutically important when the drug molecules are highly plasma protein
bound (i.e., over 90%). Although this is true of all three C drugs, the difference in their acid/base
nature significantly decreases the probability ofBa drug interaction due to plasma protein displace-
ment. Tolbutamide
Aripiprazole Losartan
5. Assume that the boxed functional groups of aripiprazole form four key binding interactions with
a serotonin receptor. Further assume that these binding interactions occur with the side chains of
Tyr, Asp, Ile, and Gln. Using this information, identify four possible binding interactions between
aripiprazole and the given amino acids. Assume that this binding interaction occurs at a physiological
6. Assume that this that this binding interaction occurs at a physiological pH of 7.4.
pH=7.4.
D
A
C
B
Aripiprazole
Answer
Answer
H
O N R4
Gln
R3
H
N
O Asp O H
H Hydrogen Bond
R1 N
R2 H O
O N
Ionic Bond
–
O
Cl Cl O
+
N N
van der Waals;
van der Waals; H H
N Hydrophobic Interaction
Hydrophobic Interaction
R6 R5
R8 OH O
N Ile
H
R7
Tyr
O
Other binding interactions are possible among these four functional groups and four amino acids.
Isoleucine could form van der Waals and hydrophobic interactions with the halogenated aromatic
ring, whereas tyrosine could form the same types of interactions with the alkyl chain. Aspartic acid
could form an ion–dipole interaction (as the ion) with the amide, whereas glutamine could form an
ion–dipole interaction (as the dipole) with the ionized tertiary amine. Please note that it is possible
for tyrosine to form hydrogen bonds with the amide and an ion–dipole interaction (as the dipole)
with the ionized tertiary amine. However, in the scenario given in this question, if tyrosine was used
to form an interaction with either the amide or the ionized tertiary amine, neither aspartic acid or
glutamine could be used to form van der Waals and hydrophobic interactions with the halogenated
aromatic ring.
2.9 Aripiprazole 141
6. Shown below are three known metabolites of aripiprazole. Identify the metabolic transformations
that would be7.required
Showntobelow
formare
each
or of the metabolites.
a phase For each metabolic transformation, indicate
II transformation.
if it is a phase I transformation or a phase II transformation.
Metabolite A
Metabolite B
Metabolite C
Answer
Answer
Metabolite A: Aromatic oxidation,
Metabolite phase oxidation,
A: Aromatic I phase I
Note: This is somewhat of an B:
Metabolite unexpected metabolite
Benzylic oxidation, because
phase I the presence of halogen substitutents
on the aromatic ring generally deactivates these rings from oxidation. The difference in this partic-
ular drug moleculeNote:
is theDue to the ability
presence of an to form a conjugated
adjacent system,
aromatic amine. thisaromatic
This secondary hydroxyl
amine group readily
can donate
electrons into the undergoes
ring via resonance andtoeither
dehydration override
form the or neutralize
following metabolite.the electronic effects of the
chloro groups, thus allowing for aromatic oxidation.
Metabolite B: Benzylic oxidation, phase I

Dehydration
Note: Due to the ability to form a conjugated system, this secondary hydroxyl groupallows
readily under-
goes dehydration to form the following metabolite. conjugation between
the amide and the
aromatic ring.
Metabolite A: Aromatic oxidation, phase I
Metabolite B: Benzylic oxidation, phase I
Note: Medicinal
142 Due to theChemistry
ability to Self
formAssessment
a conjugated system, this secondary hydroxyl group readily
undergoes dehydration to form the following metabolite.
Dehydration allows
conjugation between
the amide and the
aromatic ring.
Metabolite C: Oxidative N-dealkylation followed by oxidation of the resulting aldehyde to a carbox-

ylic acid by aldehyde dehydrogenase, phase I

Answers
2.10 Cefprozil
Cefprozil is a second-generation cephalosporin that exhibits good Chemistry

Medicinal Gram (+) activity with improved
Self-Assessment Gram
Book: (–) activity
Batch Two
as compared to the first-generation cephalosporins. Effective against the majority
Chapters of1.10
bacteria
andthat
2.10cause upper and
lower respiratory infections, as well as skin infections, cefprozil was a first-line anti-infective agent until an increase in
Chapter
the incidence of resistance and the 1.10/2.10
development of (remove bold decreased
newer agents from drug its
name)
“favored” status.
Cefprozil (Cefzil)
1. Conduct a complete structural evaluation of cefprozil and use the information in the grid to inform your
Chpater
answers to the questions that 1.10/2.10 Corrected structure (product of E transformation)
follow.
Answer NH 2 H
H H
HO N S
Function
O N
HO O Amino Acids
CH 3
O H
H H CO2 That
H Can
N S Interact with
N H2
Function Functional
O
Character N OH
HO O C H3 Interaction(s) Group via
Character Acidic, Basic, Function H-Bonding (at H H
CO2 H Possible with O H 2N S
HO
Name of Hydrophilic or Neutral ↑ Solubility Biological Target pH=7.4)
Functional and/or Provide pKa and/or at Physiological None Is N
A B O
Group Hydrophobic When Relevant ↑ Absorption pH=7.4 Acceptable CO2 H
A Phenol Hydrophilic (OH) Acidic Solubility (OH) OH: Ser,CTyr, Trp, His,
Hydrophobic (Ar) (pKa 9–10) Absorption (Ar) 2 H
N HH-bonding Thr, Cys, Asn, Gln
H (A+D)
H
Dipole–dipole S
N
Ion–dipole
O (as
N the
HO dipole)
O C H3
Ar: CO2H
van der Waals

NH 2 H Hydrophobic D
H H
F
N S π-π Stacking
E
O N
HO O CH 3
N H2 H
H H
O143 N H N S
O
O
S O N
-O O O
Continued from previous page.
Function
Amino Acids
That Can
Interact with
Character Function Functional
Group via
Character Acidic, Basic, Function Interaction(s) H-Bonding (at
or Neutral Possible with pH=7.4)
Name of Hydrophilic ↑ Solubility Biological Target
Functional and/or Provide pKa and/or at Physiological None Is
Group Hydrophobic When Relevant ↑ Absorption pH=7.4 Acceptable
B Primary amine Hydrophilic (NH2) Basic Solubility (NH2) Ion–dipole (as the ion) None
Hydrophobic (R) (pKa 9–11) Absorption (R) Ionic
C Amide Hydrophilic (CONH) Neutral Solubility (CONH) H-bonding (A + D) Ser, Tyr, Thr, Cys,
Hydrophobic (R) Absorption (R) Dipole–dipole Asn, Gln, Trp, His
dipole)
D Lactam Hydrophilic (CON) Neutral Solubility (CON) H-bonding (A) Ser, Tyr, Thr, Cys,
(cyclic amide) Hydrophobic (R) Absorption (R) Dipole–dipole Asn, Gln, Trp, His
dipole)
E Thioether Hydrophobic Neutral Absorption Hydrophobic None
van der Waals
F Carboxylic Hydrophilic (COOH) Acidic Solubility (COOH) Ion–dipole (as the ion) None
acid Hydrophobic (R) (pKa 2.5–5) Absorption (R) Ionic
G Alkene Hydrophobic Neutral Absorption Hydrophobic None

Chapter 2.10 (remove bold from drug name) van der Waals
D (four membered ring)

B
E
A
C G
Cefprozil
2. Based on the information in the structure evaluation grid, determine if cefprozil is an acidic, basic, or
amphoteric drug. Provide a brief explanation for your answer.
Answer
Cefprozil contains two acidic functional groups (phenol and carboxylic acid) and one basic functional
group (primary amine). Because this drug contains both acidic and basic functional groups, it is
considered amphoteric in nature.
2.10 Cefprozil 145
3. Cefprozil is administered orally as a tablet or liquid suspension. Consider each of the acidic and basic
functional groups and determine whether each group will be predominantly ionized or unionized
as it moves through the gastrointestinal (GI) tract, into systemic circulation, and then into the urine.
[The relevant pKa values=10, 1.7, and 7.2.] Complete the grid below.
Answer

Phenol Acidic Unionized Unionized Unionized Unionized Unionized
pKa~10
Carboxylic acid Acidic Ionized Unionized Ionized Ionized Ionized
pKa ~1.7
Primary amine Basic Ionized Ionized Likely 50%/50% Unionized Ionized
pKa~7.2 ionized/unionized
4. Given the predominant ionization state of these acidic and basic functional groups as they
traverse the GI tract and the information in the structure evaluation grid, determine in which GI
compartment(s) drug absorption could occur.
Answer
Drug absorption is enhanced as hydrophobic character is increased and as the percent unionized
increases. Cefprozil contains several hydrophobic functional groups including the aromatic ring
portion of the phenol, the thioether, and the alkenes. In the stomach (pH=1), the carboxylic acid and
the phenol will be predominantly unionized; however, the primary amine will be predominantly
ionized. In the intestine (pH=8), the phenol and the primary amine will be unionized, and both the
carboxylic acid will be primarily ionized. This means that cefprozil will always be predominantly in
an ionized form regardless of the GI location. A quick reminde—an equilibrium exists between the
ionized form and the unionized form of a drug molecule. In the case of cefprozil, there is only a very
small fraction of the drug that is completely unionized at any point in time regardless of its location
within the GI tract. When cefprozil is in its unionized form, there is sufficient hydrophobic character
to permit the drug to cross the lipid bilayer membranes of the GI tract and enter systemic circulation.
Based on this evaluation, it is possible that drug absorption can occur in both GI compartments.
5. Approximately 60% of a cefprozil dose is recovered in the urine unchanged. Because impairment in
Cefprozil
hepatic function (Cefzil)the half-life of the drug by several hours, it is likely that cefprozil under-
increases
goes a variety of metabolic transformations catalyzed by liver enzymes. For each of the metabolic
transformations A–F, identify which metabolic transformation has occurred and whether the product
Chpater
formed 1.10/2.10 Corrected
was the result structure
of a phase I or(product
phase IIofmetabolic
E transformation)
transformation.
NH 2 H
H H
HO N S
O N
HO O CH 3
O H
H H CO2 H
N S
N H2
O N OH
HO O C H3
H H
CO2 H O H 2N S
HO
N
B O CH 3
A
CO2 H
C
N H2 H
H H
N S
O N
HO O C H3
CO2H
NH 2 H D
H H
F
N S
E
O N
HO O CH 3
N H2 H
H H
O N H N S
O
O
S O N
-O O O C H3
OH O
CO2 H
NH 2 H
H H
N S
O N OH
HO O
CO2 H
Answer
Name of Transformation Phase I or Phase II

A Oxidative deamination Phase I
B Aromatic hydroxylation Phase I
C Amide hydrolysis Phase I
D Sulfate conjugation Phase II
E Allylic oxidation Phase I
F Amino acid conjugation (with glycine) Phase II
2.10 Cefprozil 147
6. Like the penicillins, the cephalosporins suffer from chemical instability of the β-lactam bond. Chem-
ical hydrolysis of this bond renders the drugs in the class of anti-infective agents inactive. This bond
is also subject to cleavage by β-lactamases (due to the presence of a nucleophilic serine side chain
[CH2OH] within the active site of the enzyme). Show how the β-lactam bond can be hydrolyzed by
chemical and enzymatic (β-lactamase) mechanisms.
Answer
Chemical Hydrolysis
OH-
Enzymatic Hydrolysis

Answers
2.11 Cetirizine
Cetirizine is a popular second-generation antihistamine used in the management of allergy symptoms. It is the
metabolic byproduct produced from the prescription antihistamine
Chapters 1.11 and hydroxyzine.
2.11 Although cetirizine is labeled as
non-sedating and is one of the preferred allergy medications for long-haul drivers, hydroxyzine causes significant
drowsiness that limits its utility in the management of typical allergy symptoms. Hydroxyzine is commonly used in
Chapter
the treatment 1.11 (remove
of pruritus (severebolded drug names)
itching).
Cetirizine
Hydroxyzine
1. Conduct a complete structural evaluation of hydroxyzine and use the information in the grid to inform
A C D E
B Hydroxyzine
149
Answer
Function
Character
Amino Acids That
Acidic, Function
Can Interact with
Basic, or
Interaction(s) Functional Group
Character Neutral Function
Possible with via H-Bonding (at
Name of Hydrophilic Provide ↑ Solubility Biological Target pH=7.4)
Functional and/or pKa When and/or at Physiological None Is
Group Hydrophobic Relevant ↑ Absorption pH=7.4 Acceptable
A Halogenated Hydrophobic Neutral Absorption Cl: None
aromatic Dipole–dipole
hydrocarbon
Medicinal Chemistry Self-Assessment
Ion–dipole (as the Book: Batch Two
dipole)1.11 and 2.11
Chapters
Ar:
van der Waals
Hydrophobic
π-π Stacking
B Aromatic Hydrophobic Neutral Absorption van der Waals None
hydrocarbon Hydrophobic
π-π Stacking
C Piperazine (two Hydrophobic (R) Basic Absorption (R) Ion–dipole (as the None (ionized at
tertiary amines) Hydrophilic (N) (pKa 9–11) Solubility (N) ion) pH=7.4)
Ionic
D Ether Hydrophobic (R) Neutral Absorption (R) H-bonding (A); Ser, Thr, Cys, Tyr, Gln,
Dipole–dipole; Asn, His, Trp Cetirizine
Hydrophilic (O) Solubility (O)
Hydroxyzine Ion–dipole (as the
dipole)
E Primary alcohol Hydrophobic (R) Neutral Absorption (R) H-bonding (A+D); Ser, Thr, Cys, Tyr, Gln,
Hydrophilic (OH) Solubility (OH) Dipole–dipole; Asn, His, Trp
Chapter 2.11 (remove bolded drug names) Ion–dipole (as the

dipole)
A C D E
B Hydroxyzine
2. Name the phase I metabolic transformation(s) that hydroxyzine undergoes to produce cetirizine.
Answer
Alcohol oxidation followed by aldehyde oxidation to the carboxylic acid.
2.11 Cetirizine 151
3. Based on your structural evaluation of both hydroxyzine and cetirizine, name ALL of the phase I
metabolic transformations possible.
Answer
• Oxidative O-dealkylation
• Oxidative N-dealkylation
• Alcohol oxidation
• Aromatic hydroxylation (less likely on halogenated aromatic hydrocarbon)
NOTE: Although there is a benzylic carbon with a hydrogen atom attached to it, benzylic oxidation
does not occur because the benzylic carbon is already directly attached to another heteroatom (N).
4. A metabolic product from a phase II metabolic transformation has been identified. Which phase II
transformations can cetirizine undergo?
Answer
The carboxylic acid can undergo phase II transformations including glucuronidation and amino acid
conjugation (with glutamic acid and glycine [major], and aspartic acid, serine, and taurine [minor]).
(NOTE: the glucuronide conjugate is the metabolite that has been identified.)
5. Review the structure of cetirizine (pKa=2.9 and 8.3) and identify all of the acidic and basic functional
groups present. Determine the predominant ionization state of each functional group as it travels
through several compartments of the body after oral administration. Complete the table below.
Answer

Tertiary amine Basic Ionized Ionized Ionized Ionized Ionized
(piperazine) pKa 8.3
Carboxylic acid Acidic Ionized Unionized Ionized Ionized Ionized
pKa 2.9
6. Provide a structural rationale for why hydroxyzine is classified as a sedating antihistamine and cetiri-
zine is categorized as a non-sedating antihistamine.
Answer
Hydroxyzine contains functional groups that contribute to the overall hydrophobic character of the
molecule (e.g., aromatic hydrocarbon, halogenated aromatic hydrocarbon, aliphatic alkane), as well
as functional groups that contribute to the hydrophilic character of the molecule (e.g., ether, primary
alcohol, and tertiary amines/piperazine). The hydrophilic character of the molecule enhances its
water solubility, whereas the hydrophobic character enhances its ability to be absorbed across lipid
bilayer membranes. At pH=7.4, the tertiary amine will be predominantly in its ionized form which
will further increase the water solubility of the molecule.
The hydrophilic character contributes to the ability of the drug to be distributed in the body in the
aqueous plasma. The hydrophobic character contributes to the ability of the drug to be absorbed
across the membranes of the gastrointestinal tract and eventually across the blood–brain barrier. It
is important to remember that the tertiary amine (one of the two) will be predominantly ionized at
physiological pH. Because an equilibrium exists between the ionized and unionized form of the drug,
some fraction of the drug will be unionized at any point in time and, therefore, can cross the blood–
brain barrier and have an effect on the histamine receptors.
NOTE: When activated, the histamine receptor in the brain is responsible for wakefulness. When
hydroxyzine interacts with this receptor, it prevents histamine from binding to and activating its
receptor. As a result, the feeling of wakefulness is very limited, and the patient feels sleepy.
Cetirizine contains a carboxylic acid instead of the primary alcohol found in hydroxyzine. The carbox-
ylic acid significantly increases the water solubility of cetirizine as compared to hydroxyzine. The
carboxylic acid is also predominantly ionized at physiological pH. Although there is an equilibrium
between the ionized and unionized forms of the tertiary amine and of the carboxylic acid, the overall
percent of cetirizine in which both functional groups are unionized is especially small. As a result,
very, very little of a cetirizine dose can cross the blood–brain barrier and interact with the histamine
receptors. Because the central histamine receptors can still be activated, the feeling of wakefulness
remains, and the patient does not feel sleepy.
Answers
2.12 Chlorpropamide and

Other Sulfonylureas

Shown below are the structures of tolbutamide and chlorpropamide. These drug molecules are used in the treat-
ment of type 2 diabetes mellitus. They stimulate the release of insulin from the pancreatic β-cells by interacting with
Shown below are the structures of tolbutamide potassium channels.
adenosine triphosphate (ATP)-sensitive potassium channels.
Shown below are the structures of tolbutamide potassium channels.
1. uncommon
1. It is not It is not uncommon for patients
for patients with2type
with type 2 diabetes
diabetes to beate that diagnosed
dually a drug interaction could occur?and
with hypertension
require additional pharmacotherapy. In this scenario, it is possible for drug interactions to occur if the
prescribed combination therapy is not appropriately evaluated. Angiotensin II receptor antagonists,
commonly known as Tolbutamide
angiotensin II receptor blockers (ARBs), are often Chlorpropamide
used to treat hypertension.
Losartan (shown below) is an ARB, and similar to tolbutamide and chlorpropamide, is highly plasma
protein bound. If losartan was selected for use in a patient who is already taking tolbutamide or chlor-
1. It is not uncommon for patients with type 2 diabetes ate that a drug interaction could occur?
propamide, would you anticipate that a drug interaction could occur?
Losartan
Answer Losartan
Plasma protein binding interactions (also known as that a drug interaction could occur.
Answer Sulfonylurea Sulfonylurea

Answer
Plasma protein binding interactions (also known as plasma protein displacement interactions) occur due
to the nonspecific
Plasma nature interactions
protein binding of the plasma proteins
(also known that bind
as that and interaction
a drug transport drug
couldmolecules.
occur. There are two
key concepts to consider when evaluating the probability of a plasma protein binding interaction. First,
these types of interactions are therapeutically important only when the drug molecules are highly plasma
protein bound Sulfonylurea
(i.e., over 90%). Second, acidic drugs primarily bind Sulfonylurea
to albumin, whereas basic drugs
primarily bind to α1-glycoprotein. The information provided in the question indicates that all of these
compounds are highly Chlorpropamide
plasma protein bound; therefore, we need to evaluate Tolbutamide
the acid/base nature of
153
Losartan
these drug molecules. The structures of tolbutamide and chlorpropamide contain an acidic sulfonylurea,
whereasAnswer
the structure of losartan contains an acidic tetrazole. Because both of these drug molecules
are acidic and are
Plasma highly
protein plasma
binding protein bound
interactions to albumin,
(also known as that athere
drugisinteraction
a high probability that a drug
could occur.
interaction could occur.
Sulfonylurea Sulfonylurea
Chlorpropamide Tolbutamide
Acidic protons
are circled
Tetrazole
Losartan
2. The normal pKa range for sulfonylureas is 5 to 6. When comparing the pKa values of chlorpropamide
and tolbutamide, it is found that the sulfonylurea of one of these drug molecules has a pKa=5.4 and
the other has a pKa=4.9. Evaluate the structures of these two drug molecules, assign the pKa values to
the correct molecules, and provide an explanation for the difference in pKa values.
2. The normal pKa range forrect molecules, and provide an explanation for the difference in pKa values.
Answer
Answer evaluation of chlorpropamide and tolbutamide reveals two chemical differences.
A structural
Three carbon Four carbon

aliphatic chain aliphatic chain
Tolbutamide
Chlorpropamide Methyl group
Halogen
The differences in the length of the aliphatic hydrocarbon chains would not be expected to have a
major effect on the acidity of the sulfonylurea because they would both donate electrons through
3.induction.
Using your answer
Thus, from question
the difference 2, that
in the pKawill be ionized
values can beatattributed
an intestinal pH of
to the 6.1.
electronic differences
between the halogen and the methyl group. Halogens act as electron withdrawing groups through
Answer
induction, whereas the methyl group acts as an electron donating group through induction. Because
acidic functional groups (i.e., sulfonylureas) form anions once the proton leaves, adjacent functional
groups that are electron withdrawing will increase acidity. Adjacent functional groups that are
[Base~Form]
pH =~pK
electron a +log ~
donating will decrease acidity. Thus, the sulfonylurea group present within the structure
[Acid~Form]
[Base~Form]
2.12 Chlorpropamide and Other Sulfonylureas 155
of chlorpropamide would be expected to be more acidic (pKa=4.9) than the one present within the
structure of tolbutamide (pKa=5.4) due to the electron withdrawing character of the halogenated
aromatic ring.
3. Using your answer from question 2, calculate the percent of tolbutamide that will be ionized at an
intestinal pH=6.1.
Answer
As determined in question 2, the pKa of the sulfonylurea groups of tolbutamide is 5.4. To solve this
problem, we need to use the Henderson-Hasselbalch equation. Because the functional group is acidic,
the ionized form (R-SO2N–CO-R) is the base form and the unionized form (R-SO2NHCO-R) is the acid
form.
[Base Form]
pH = pK a +log
[Acid Form]
[Base Form]
6.1= 5.4 +log
[Acid Form]
[Base Form]
0.7 = log
[Acid Form]
5.01=
[Base Form] or 5.01 = [Base Form]
[ Acid Form] 1 [ Acid Form]
This ratio indicates that for every one molecule that contains the functional group in the acid (or
unionized) form, there are 5.01 molecules that contain the functional group in the base (or ionized)
form. The following equations can then be used to correctly calculate the percent of the molecules
that are ionized and the percent that are unionized.
5.01 molecules in base form + 1.0 molecule in acid form = 6.01 total molecules
Base form = Ionized form and Acid form = Unionized form
5.01 Molecules in Ionized Form
Percent in Ionized Form = ×100% = 83.4%
1 Molecule in Unionized Form
Percent in Unionized Form = ×100% = 16.6%
The question asks for the percent that will be ionized, so the correct answer is 83.4%.
4. The mechanism of action of this class of drugs involves the ability to interact with the ATP-sensitive
potassium channels in the pancreas. Using the structure of tolbutamide, identify the types of binding
interactions that would be possible between its functional groups and a protein ion channel. Also
identify amino acids present within this ion channel whose side chains could participate in the inter-
actions identified. Assume a plasma pH=7.4 for all ionizable functional groups.
4. The mechanism of action of this class of to interact with the ATP-sensitive potassium groups.
Answer
Answer
B
A D
C
Tolbutamide
Aminothan
5. Tolbutamide has a half-life of 4.5 to 6.5 hourssignificantly longer half-life Acids Capable of Forming
tolbutamide.
Functional Group Types of Binding Interactions Specific Bond
Answer
A Phenyl ring; aromatic ring; van der Waals; Hydrophobic Tyr, Phe, Trp (better bond*); Val, Leu, Ile, Met, Ala
aromatic hydrocarbon
B Sulfonylurea (1) Ionic (1) Lys, Arg, His**
Metabolism of Tolbutamide
(2) Ion–Dipole (as the Ion) (2) Ser, Thr, Tyr, Cys, Asn, Gln, His**
C Nitrogen atom of sulfonylurea (1) Ion–Dipole (as the Dipole) (1) Asp, Glu (with the hydrogen); Arg, Lys, His**
not involved in resonance Z oxidation (with the nitrogen)
(2) Dipole–Dipole (2) Ser, Thr, Tyr, Cys, Asn, Gln, His**
(3) Hydrogen Bond (Donor and/or Acceptor) (3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His**
D Alkyl group; alkyl chain; van der Waals; Hydrophobic Val, Leu, Ile, Met, Ala (better bond*); Tyr, Phe, Trp
aliphatic chain
Z-1 oxidation
*Due to steric fit, stronger van der Waals interactions occur when aromatic rings interact with aromatic
rings and when aliphatic chains interact with aliphatic chains; however, all of the listed amino acids could
Benzylic
possibly interact with the boxed functional group.
oxidation
**Histidine is primarily unionized at a pH=7.4. The small fraction that is ionized could participate in
an ion–dipole interaction with a partially negative atom, while the unionized fraction can serve as a
hydrogen bond donor or acceptor. It can also serve as the dipole in an ion–dipole bond.
1. Alcohol
dehydrogenase
5. Tolbutamide has a half-life of 4.5 to 6.5 hours, whereas chlorpropamide has a half-life of 36 hours.
Propose a chemical/structural reason why chlorpropamide has a significantly longer half-life than
2. Aldehyde
tolbutamide. dehydrogenase
Answer
As discussed in question 2, there are two structural differences between tolbutamide and chlor-
propamide: the length of the aliphatic chain and the para substituent on the phenyl ring. Both drug
Metabolism of Chlorpropamide
molecules can undergo π and π-1 oxidation of their respective aliphatic chains. Metabolism at these
sites would be expected to be similar; however, the additional carbon atom present in tolbutamide
may cause the butyl side chainZto be less sterically hindered and more susceptible to oxidation than
oxidation
the propyl chain present in chlorpropamide. The more significant difference is metabolism of the
para substituent. The para methyl group present within the structure of tolbutamide can undergo
benzylic oxidation followed by two additional oxidative transformations to convert the benzylic
hydroxyl group into a para carboxylic acid. The para chloro group present within the structure of
chlorpropamide deactivates oxidation of the aromatic ring due to its electron withdrawing effects.
As a result, tolbutamide hasZ-1 oxidation
a much shorter half-life than chlorpropamide.
Electron withdrawing
halogen prevents
aromatic oxidation
Tolbutamide
5. Tolbutamide has a half-life of 4.5 to 6.5 hourssignificantly longer half-life and

2.12 Chlorpropamide thanOther
tolbutamide.
Sulfonylureas 157
Answer
Metabolism of Tolbutamide
Z oxidation
Z-1 oxidation
Benzylic
oxidation
1. Alcohol
dehydrogenase
2. Aldehyde
dehydrogenase
Metabolism of Chlorpropamide
Z oxidation
Z-1 oxidation
Electron withdrawing
halogen prevents
aromatic oxidation
(Lipid soluble)

Sulfonylureas)
6. Glyburide is a second-generation sulfonylurea that is structurally similar to chlorpropamide and
tolbutamide. Shown below are the structures of glyburide and one of its known metabolites. Identify
the metabolic pathways that are required to produce this metabolite.
Cl O
O O
S N N
H H
N O
H
O
H3C Glyburide
O OH
O O
H3C S N N
H H
N O
H
Answer
This metabolite is formed as the final product of three metabolic transformations. Oxidation of
the alicylic ring produces the secondary alcohol. Hydrolysis of the initial amide bond of glyburide
produces a primary amine that can undergo phase II acetylation. In most cases, further metabolism of
a primary amine involves oxidative deamination; however, there are some cases where the primary
amine is acetylated. Please note that the oxidation of the alicyclic ring is independent of the coupled
hydrolysis and acetylation transformations.

Answers
2.13 Dabigatran Etexilate
Thrombin is the enzyme responsible for catalyzing the conversion of fibrinogen to fibrin. The production of fibrin is
important in the formation of sturdy blood clots. As you might expect, inhibition of thrombin prevents the forma-
tion of fibrin. As shown in the diagram below, a catalytic triad of amino acids (Asp, His, Ser) found in the active site
of thrombin is responsible for hydrolyzing a key peptide bond found within fibrinogen. Orientation of fibrinogen in
the active site ofChapters
thrombin1.13/2.13
relies on the interaction
Concern about of
Hisa key tri-peptide
(revised diagramsequence (D-Phe-Pro-Arg)
+ removed bolded names) found within the
structure fibrinogen with key amino acids in the enzyme active site.
Chapters
Dabigatran 1.13/2.13
etexilate Concern about
is administered His (revised
as a prodrug. diagram
In its + removed
active form, bolded
dabigatran names)is an orally active direct
etexilate
thrombin inhibitor used in the prevention of stroke and blood clots in patients diagnosed with atrial fibrillation.
Thrombin catalyzed
amide hydrolysis
Thrombin catalyzed
amide hydrolysis
Fibrin
Fibrin
159
3
1. Conduct a complete structural evaluation of dabigatran etexilate (prodrug) and use the information
in the grid to inform your answers to the questions that follow.
Answer
Function
Character
Function
Amino Acids That
Acidic, Basic, Can Interact with
Character Function Interaction(s)
or Neutral Functional Group
Possible with
Name of Hydrophilic Provide pKa ↑ Solubility Biological Target at via H-Bonding (at
Functional and/or When and/or Physiological pH=7.4)
A Ester Hydrophilic (COO) Neutral Solubility (COO) H-bonding (A) Ser, Thr, Cys, Tyr, His,
Hydrophobic (R) Absorption (R) Dipole–dipole Asn, Gln, Trp
Ion–dipole (as the dipole)
B Amide Hydrophilic (CON) Neutral Solubility (CON) H-bonding (A) Ser, Thr, Cys, Tyr, His,
C Pyridine Hydrophilic (N) Basic Solubility (N) Pyridine N: Ser, Thr, Cys, Tyr, His,
(Azine) Hydrophobic (R) pKa=1–5 Absorption (R) H-bonding (A) Asn, Gln, Trp
Dipole–dipole
dipole)
(R):
Hydrophobic
van der Waals
π-π Stacking
D Benzimidazole Hydrophilic (imid- Basic Solubility (imid- Imidazole (N atoms): Ser, Thr, Cys, Tyr, His,
azole N atoms) pKa=1–5 azole Ns) H-bonding (A) Asn, Gln, Trp
dipole)
Ar:
Hydrophobic
van der Waals
π-π Stacking
E Aromatic amine Hydrophilic (NH2) Basic Solubility (NH2) NH2: Ser, Thr, Cys, Tyr, His,
(aniline) Hydrophobic (Ar) pKa=2–5 Absorption (Ar) H-bonding (A+D) Asn, Gln, Trp
Dipole-dipole
dipole)
Ar:
Hydrophobic
van der Waals
π-π Stacking
F Carbamate Hydrophilic (OCON) Neutral Solubility (OCON) H-bonding (A) Ser, Thr, Cys, Tyr, His,
Chapters 1.13/2.13 (removed bolded text)
A B E F
D
2. Dabigatran etexilate is a non-peptidomimetic prodrug. Provide a brief rationale for the value of
converting an active drug into
Chapters a prodrug.
1.13/2.13 (removed bold drug name)
Answer
There are situations (e.g., the need to enhance water or lipid solubility) when it is therapeutically
beneficial to administer drug molecules that have been covalently modified to produce inactive (or
very weakly active) analogs (i.e., prodrugs) (see Chapter 5 in Basic Concepts in Medicinal Chemistry).
Bioactivation of these prodrugs via rapid metabolic transformation (e.g., ester hydrolysis) can occur
via chemical or enzymatic mechanisms. Typically metabolic activation (via hydrolysis) occurs within
the gastrointestinal (GI) tract. Given that esterases are ubiquitous, release of the active drug can
occur in the plasma or even at the target tissue.
In the case of dabigatran etexilate, a carboxylic acid is converted to an ester and an amidine is
converted to a carbamate. In both cases, the modified functional group is significantly more lipid
soluble than the parent functional group. Dabigatran is not absorbed orally, so it is necessary to
develop a prodrug analog to allow for sufficient absorption from the GI tract.
3. Dabigatran etexilate rapidly undergoes two esterase-catalyzed hydrolytic reactions to the active drug
dabigatran. Show the products from each of the esterase-catalyzed
Dabigatran etexilate mesylatehydrolytic reactions that occur in
the plasma.
Chapter 2.13 (removed bolded drug names)

Answer
O O H NH 2
N N O
H 3C O N
N
N O(CH2)5CH3
N
C H3
Dabigatran Prodrug
O O H N H2
N N O
HO N
N
N O(CH2 )5 CH3
N
C H3
O O H N H2
N N
H 3C O N
NH
N N
C H3
O O H N H2
N N
HO N
NH
N N
CH 3

4. In its active form, dabigatran mimics the D-Phe-Pro-Arg tripeptide sequence, but does not contain a
peptide backbone (non-peptidomimetic). Review the tripeptide sequence drawn below noting that
there are numbers 1–3 that indicate where each amino acid is located in the sequence. Determine the
4. ofIninteractions
types its active form, dabigatran
possible with mimics
each ofthe
theD-Phe-Pro-Arg tripeptide
amino acid side chains. chains.
NH O
3
H 2N N R
H O N
O
H
H 2N 1 2
N

Answer
Types of Interactions Possible
5. Review side chain indicated.
D-Phe (1) Hydrophobic
van der Waals
π-π Stacking
Pro (2) A
Hydrophobic B E F
van der WaalsO O
D H N H2
Arg (3) Ion–dipole (as the ion) N N
HO N
Ionic NH
N
N
C C H3
5. Review the structure of dabigatran and determine which of the boxed groups will likely mimic the
interactions found within the D-Phe-Pro-Arg tripeptide sequence. Given the three-dimensional
nature of both peptides and small molecules, it is important to remember that the functional groups
within dabigatran do not need to lineActive
up in the
formsame order. Using the table provided to guide your
ofname)
Dabigatran
Chapter 2.13 (remove bolded drug
analysis, place a Yes or No in each box to indicate whether the functional group could mimic the
amino acid side chain indicated.
6. Dabigatran salt. Provide a brief rationale for the value of administering the salt form of a drug.
A B E F
D

5. Review side chain indicated.
A B E F
Answer
O O H N H2
D
D-Phe mimic Pro mimic Arg mimic N
N
A No H O No N No NH
B No No No N
N
C Yes Yes C No C H3
D Yes Yes No
E Yes Yes No
F No No Yes
6. Dabigatran etexilate is formulated as a mesylate salt. Provide a brief rationale for the value of
administering the salt.
6. Dabigatran salt form of aa brief
Provide drug.rationale for the value of administering the salt form of a drug.

Answer
Mesylate salts are considered water soluble organic salts. The use of water soluble organic salts is
one method to enhance the overall water solubility of your drug. This is accomplished by increased
solvation and dissolution of the drug. The use of a water soluble organic salt also helps to ensure an
adequate water/lipid balance necessary for oral absorption. As we have already determined in the
structure evaluation grid, there is some hydrophobic character present, but there is also substantial
hydrophilic character.

Answers
2.14 Fenofibrate and Gemfibrozil
Fenofibrate is a member of the fibrate class of anti-hyperlipidemic agents. It is used as adjunctive therapy to diet in the
management of dyslipidemias, including in the treatment of severe hypertriglyceridemia. The specific mechanism(s)
by which fenofibrate decreases triglyceride and total cholesterol levels, as well as increases the levels of high density
lipoproteins (HDL), is unknown. What1.14 we
anddo2.14
know is that
(drug namethe–decrease
remove in very low density lipoproteins (VLDLs)
bold)
results from fenofibrate stimulation of lipoprotein lipase.
1. Conduct a complete structuralLetter

evaluation of fenofibrate
“C” – add bold and use the information in the grid to inform
Answer
Function
Amino Acids That

Character Function
Can Interact with the
Interaction(s) Functional Group via
Character Acidic, Basic, Function
Possible with Hydrogen Bonding
or Neutral
Name of Hydrophilic C
↑ Solubility Biological Target Interactions at
Functional and/or Provide pKa and/or at Physiological pH=7.4
A Halogenated Hydrophobic 2.14Neutral
– remove bold from label
Absorption Hydrophobic None
aromatic van der Waals
hydrocarbon
π-π Stacking
B F
Dipole–dipole
A C D Ion–dipole (as the
dipole)
B Ketone Hydrophilic (CO) Neutral Solubility (CO) H-bonding (A) Ser, Thr, Tyr, Cys, Asn, Gln,
Hydrophobic (R) Absorption (R) Dipole–dipole His, Trp
E Ion–dipole (as the
dipole)
Fenofibrate

165
O

C Aromatic Hydrophobic Neutral Absorption Hydrophobic None
hydrocarbon Fenofibrate Gemfibrozil
van der Waals
Letter “C” – add bold π-π Stacking
Letter
D “C”Ether– add boldHydrophilic (O) Neutral Solubility (O) H-bonding (A) Ser, Thr, Tyr, Cys, Asn, Gln,
dipole)
E Aliphatic Hydrophobic Neutral Absorption Hydrophobic None
alkane van der Waals
F Ester Hydrophilic Neutral Solubility (COO) H-bonding (A) Ser, Thr, Tyr, Cys, Asn, Gln,
C
(COO) Absorption (R) Dipole–dipole His, Trp
HydrophobicC(R) Ion–dipole (as the
2.14 – remove bold from label dipole)
.
B F
B
AF C D
A C D
E
E Fenofibrate
Fenofibrate
2. Fenofibrate is administered2.14
as a– prodrug
remove bold
and from label hydrolysis to the active drug. Draw the
undergoes
active drug. Provide a brief
2.14 – remove bold from label rationale for the value of administering fenofibrate as a prodrug.
Answer O O C H3 O
Ester
O OHydrolysis O O
O O C H3
O C H3
Ester
O O H3C
H3 C C H3
Hydrolysis
O CH OH
Cl 3 Cl
H3C C H3 H3C C H3
Cl Cl
Inactive Active
Inactive Active
There are situations (e.g., the need to enhance water or lipid solubility) when it is therapeutically
beneficial to administer drug molecules that have been covalently modified to produce inactive (or
very weakly active) analogs (i.e., prodrugs) (see Chapter 5 in Basic Concepts in Medicinal Chemistry).
Bioactivation of these prodrugs via rapid metabolic transformation (e.g., ester hydrolysis catalyzed
by esterases) can occur via chemical or enzymatic mechanisms. Typically metabolic activation occurs
within the gastrointestinal (GI) tract, but given that esterases are ubiquitous, release of the active
drug can occur in the plasma or even at the target tissue.
In the case of fenofibrate, a carboxylic acid is converted to an ester to form a prodrug. The resulting
modified functional group (now an ester) is significantly more lipid soluble than the parent func-
tional group (originally a carboxylic acid). The calculated log P for fenofibrate is 5.24, which suggests
that the prodrug is lipophilic.
2.14 Fenofibrate and Gemfibrozil 167
3. The calculated
1.14 andlog P for
2.14 fenofibrate
(drug is 5.24,
name – remove whereas the calculated log P for gemfibrozil is 3.9.
bold)
Provide a structural rationale for the difference in this pharmacokinetic property.
3. The calculated for difference in this pharmacokinetic property.
Answer
Letter “C” – add bold
A larger calculated log P value reflects the presence of additional hydrophobic character. Let’s see
if that statement pans out as we evaluate each of these molecules. The structure evaluation grid
for fenofibrate reveals that there are several functional groups that contribute to its hydrophobic
character including the halogenated aromatic hydrocarbon, the aromatic hydrocarbon, and both
aliphatic alkanes. Evaluation of gemfibrozil reveals hydrophobic character from a dimethyl substi-
tuted aromatic hydrocarbon and an aliphatic alkane. The larger calculated log P value for fenofibrate
is justified by the presence of significantly more functional groups with hydrophobic character.
Fenofibrate
4. From an elimination perspective, 60% of a fenofibrate dose is foundGemfibrozil
in the urine and 25% is found
C(drug name – remove bold)
in the feces. The active1.14
form and
of 2.14
fenofibrate undergoes both phase I and phase II metabolic trans-
formations. The phase II conjugate is eliminated in the urine. Oxidative metabolism does not occur.
Evaluate each of the metabolic products and determine if it is the conjugate that is eliminated in the
4. From anremove
2.14 – elimination
bold NOT
from occur).
label
urine (that does occur), the product of a non-oxidative phase I transformation (that does occur), or
the product of an oxidative phase I transformation (that does NOT occur).
B F
O O
A C D
HO O
OH
H3 C Fenofibrate
C H3 Gemfibrozil
Cl
E
A “C” – add bold
Letter B
Fenofibrate
O O C H3 O O
Ester
O O
O C H3 Hydrolysis OH
H3C C H3 C
C H3C C H3
Cl Cl
Answer
5. Provide
Nameaofstructural
Metabolicrationale
Inactive for why oxidative O-dealkylation
Transformation Type of Productdoes not occur. Active
A Aromatic hydroxylation Product of oxidative transformation (does not occur)
Answer: B
B Ketone reduction ProductF
of non-oxidative transformation (does occur)
C Glucuronide conjugation
A C D Product of conjugation transformation (does occur)
1 2
E
C
Answer:
Answer
1 2
Oxidative O-dealkylation transformations occur with ethers that have at least one α-carbon (adja-
cent carbon atom) with at least one hydrogen atom attached. Evaluation of the ether found within
the structure of fenofibrate reveals that one of the carbons (#1) attached to the ether oxygen atom
is part of an aromatic ring. It does not have a hydrogen atom attached to it. Carbon #2, attached
to two aliphatic alkanes (methyl groups) and a carboxylic acid, also does not have a hydrogen atom
attached to it. Because neither of the α-carbons has at least one hydrogen atom attached to it, this
ether is not subject to oxidative O-dealkylation.
6. Fenofibrate and gemfibrozil have dramatically different elimination half-lives (20–22 hours and 1.5
4 and 2.14 (drug name – remove bold)
hours respectively). Identify the possible metabolic transformations for gemfibrozil and provide a
justification for the significant difference in this pharmacokinetic parameter.
Answer
er “C” – add bold
Possible phase I metabolic transformations:
• Benzylic oxidation (two different locations)*
• Oxidative O-dealkylation
• Aromatic hydroxylation (multiple)
*Note: Each benzylic hydroxyl group can be further oxidized to carboxylic acids.
Possible phase II conjugation transformations:

C
• Glucuronide conjugation
• Amino acid conjugation (with glutamine, glycine, arginine or taurine)
4 – remove bold from label
The difference in aromatic substituents between the two drugs has a large impact on the number of
B potential phase IFtransformations that produce more water soluble metabolites. Oxidative O-
dealkylation not only generates more water soluble products, but also splits gemfibrozil in half,
A C
causing D deactivation. Based on this assessment, it is no surprise that there is a difference in the
drug
elimination half-lives of these two drugs and that gemfibrozil is eliminated much more rapidly.
E
Fenofibrate
Answers
O O
O
OH
Cl
H3C C H3
2.15 Fluvoxamine
Fenofibric Acid
Fluvoxamine is an inhibitor of the serotonin reuptake transporter (SERT) and prevents the reuptake of serotonin
at the presynaptic membrane in the central nervous
1.15 and system.
2.15 – remove It is indicated
bold for use in the treatment of depression.
from label
Fluvoxamine is structurally unique relative to the rest of the serotonin selective reuptake inhibitor class of drugs.
A
B
C D
Fluvoxamine
1. Conduct a structural evaluation of fluvoxamine, focusing on the boxed functional groups, and use the
information in the grid to inform your answers to the questions that follow.
Answer F3 C
Function
O
Character C H3 Amino Acids That
Function
NH3 O Interact with the
Can
Acidic, Basic, N
–
O O
O Interaction(s) Functional Group via
Character or Neutral Function
Provide ↑ Solubility O H at
Interactions
Name of Hydrophilic
Fluvoxamine maleateBiological Target pH=7.4
Functional and/or pKa When and/or at Physiological
A Halogenated Hydrophilic (F) Neutral Solubility (F) Dipole–dipole Ser, Thr, Tyr, Cys, Asn, Gln,
aliphatic alkane Hydrophobic (R) Absorption (R) H-bonding (A) Trp, His
dipole)
B Aromatic hydro- Hydrophobic Neutral Absorption Hydrophobic None
carbon van der Waals
π-π Stacking
C Aliphatic alkane Hydrophobic (R) Neutral Absorption Hydrophobic None
van der Waals
169
A
B
C D
D Ether Hydrophilic (O) Neutral Solubility (O) H-bonding (A) Ser, Thr, Tyr, Cys, Asn, Gln,
E
dipole)
E Primary amine Hydrophilic (NH2) Basic Solubility (NH2)
Fluvoxamine Ion–dipole (as the ion) Ser, Thr, Cys, Tyr, Asn, Glu,
Hydrophobic (R) pKa 9–11 Absorption (R) Ionic His, Trp
1. Conduct a to the questions that follow.

2. Fluvoxamine is marketed as a single isomer. Is the product sold as a single enantiomer, diastereomer,
2. Fluvoxamine
or geometric is isomer?
isomer? Provide aProvide a brief rationale
brief rationale for yourforanswer.
your answer.
F3 C O O
F3 C
O
1' O OH
1' 2' O
2' C HH3 C
3 C H3 C H3
Cl N NH 2 1N
2 O H 2N 2
1 O
A Fenofibric Acid B
Answer
There are no chiral carbon atoms present; therefore, there are no enantiomeric or diastereomeric
3. Fluvoxamine is properties of the drug?
isomers possible.
Geometric isomers are A not mirror images of one another and are not superimposable (see Chapter
B Chemistry). These isomers typically occur in the presence of a
7 in Basic Concepts in Medicinal
carbon–carbon double bond, where the double bond causes conformational restriction and forces
C in one of twoDorientations. In the case of fluvoxamine, there
the bond substituents to be positioned
is a carbon–nitrogen double bond present. When evaluating isomer A, the 1' and 1 substituents
are located on opposite sides of the carbon–nitrogen double bond. This represents the trans- or
E-geometric isomer. When evaluating isomer B, the 1' and 1 substituents are located on the same side
E
of the carbon–nitrogen double bond. This represents the cis- or Z-geometric isomer. The marketed
product is the E-geometric isomer.
Fluvoxamine
Fluvoxamine maleate
3. Fluvoxamine is formulated as a maleate salt. What type of salt is a maleate salt, and what type of
1.15 and
properties does it confer to2.15 – remove
the overall bold fromof
properties label
the drug?
F C
4. Fluvoxamine is3well absorbed, provide a rationale for these pharmacokinetic properties.
O
C H3
N NH3 – O
O O
O
OH
Fluvoxamine maleate
2.15 Fluvoxamine 171
Answer
Maleate salts are water soluble organic salts. Water soluble organic salts generally enhance overall
drug water solubility (see Chapter 5 in Basic Concepts in Medicinal Chemistry). Maleate salts typically
demonstrate enhanced solvation and dissolution as compared to their free base forms. This is excep-
tionally beneficial in the preparation of parenteral, nasal, and ophthalmic dosage forms where the
delivery of small volumes of highly concentrated solutions is necessary.
4. Fluvoxamine is well absorbed and has an oral bioavailability of ~50%. Using the information found in
the structure evaluation grid, provide a rationale for these pharmacokinetic properties.
Answer
Orally administered drugs must strike a balance between having enough hydrophilic character to
promote dissolution and solubility in the aqueous contents of the gastrointestinal (GI) tract, and
sufficient hydrophobic character to allow for absorption across the lipid bilayer membrane. Fluvox-
amine has a fluorinated aliphatic alkane, an ether, and an ionized primary amine that contribute
to the overall hydrophilic character of the drug. An aromatic hydrocarbon and aliphatic alkane
contribute to the overall hydrophobic character of the drug. Based on this evaluation, it is no surprise
that the drug undergoes rapid dissolution and solvation in the aqueous contents of the GI tract.
Although it appears that there is only a moderate amount of hydrophobic character, this appears to
be sufficient to allow for absorption across the lipid bilayer membrane.
5. A number
5. A of fluvoxamine
number metabolites
of Evaluate have
each of the been
which identified,
metabolic all of whichhas
transformation demonstrate
occurred. little or no
pharmacological activity. Evaluate each of the metabolic products drawn below and identify which
metabolic transformation has occurred.
A B
C D
F
E
Answer

A Oxidative deamination
B Aromatic hydroxylation
C Oxidative O-dealkylation
D Oxidative O-dealkylation followed by alcohol oxidation
E Allylic oxidation*
F Acetylation
*Note: This carbon–nitrogen double bond acts similarly to a carbon–carbon double bond. If a carbon
substituent attached to this carbon–nitrogen double bond bears a hydrogen atom, then it can
undergo oxidation. In this case, there is only one carbon substituent that fulfills that criterion, and
there is only one location possible for an allylic oxidation to occur.
6. Fluvoxamine is a strong inhibitor of CYP1A2, CYP3A4, and CYP2C19. These enzyme isoforms catalyze
a number of the phase I oxidative metabolic transformations. Several of the benzodiazepines (used
in the treatment of anxiety), including the very popular alprazolam, rely heavily on hepatic oxidation
for metabolic inactivation and elimination. Other benzodiazepines, including the equally popular
lorazepam, rely on glucuronide conjugation for metabolic inactivation and elimination. Which
combination of drugs, fluvoxamine + alprazolam or fluvoxamine + lorazepam, is the most likely to
generate an enhanced anxiolytic effect?
Answer
Fluvoxamine inhibits several of the metabolism isoforms that catalyze oxidative metabolic transforma-
tions. Alprazolam relies on hepatic oxidation for metabolic inactivation and elimination. If fluvox-
amine inhibits the same enzymes that alprazolam relies on for hepatic oxidation, then the levels of
active alprazolam will exist for a longer period of time than expected. With more alprazolam avail-
able to produce an anxiolytic effect for a longer period of time, it is likely that an enhanced anxio-
lytic effect will be observed.
Because lorazepam relies on a different set of enzymatic isoforms for glucuronide conjugation, the
co-administration of fluvoxamine will have little or no effect on the metabolic inactivation and elimi-
nation of lorazepam, and an enhanced anxiolytic effect will not be observed.
Answers
2.16 Haloperidol
Shown below is the structure of haloperidol. Six of its functional groups have been identified.
E
D
C
F
B
1. Using 1.
the Using
table below,
the se. identify the six boxed functional groups. For each of the functional groups you
identified, indicate if it is hydrophilic or hydrophobic in character. Also provide a brief explanation for
2. Based on their electronic induction.
your response.
Answer3. Using the in pH environments of 1.7, 5.5, 6.0, 7.4, and 8.5.
Answer
A The structure
Halogen; fluorineof haloperidol contains only
Effects canone
vary;basic functional
fluorine can act as agroup and
hydrogen noacceptor;
bond acidic functional groups.
however, studies have
shown that the substitution of a hydrogen atom with a fluorine atom tends to slightly
enhance lipid solubility.
B Ketone Tertiary Hydrophilic
amine due to its ability to act as a hydrogen bond acceptor.
OH
C Alkyl group; alkyl chain; aliphatic chain Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional
groups enhance lipid N
solubility.
D Tertiary amine Hydrophilic due to its ability to ionize (form an ion–dipole interaction with water) and to
F participate in hydrogen bonding (acceptor) in its unionized form.
Cl
E Tertiary hydroxyl group; tertiary alcohol O due to its ability to form hydrogen bonds as either a donor or an acceptor.
Hydrophilic
F Phenyl ring; aromatic ring; aromatic Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional
hydrocarbon groups enhance lipid solubility.
4. Shown below is a structural analog can enhance the duration of haloperidol.

groups A, C, and E are electron withdrawing or electron donating. Additionally, identify if this effect is
Answer
• Functional Group A is a halogen. Because all halogens are more electronegative than an adjacent
aromatic ring, the fluorine atom acts as an electron withdrawing group through induction.
• Functional Group C is an alkyl group and has a lower electronegativity than the oxygen atom of the
ketone or the nitrogen atom of the tertiary amine; therefore, it acts as an electron donating group
through induction.
173
E
174 Medicinal Chemistry Self Assessment D

C
E
A D
C
• Functional Group E is a tertiary hydroxyl group. Based on its position in the molecule and the
fact that it is notAdirectly attached to an aromatic ring, it acts as an electron withdrawing group
through induction. F
B
F
1. the
3. Using Using B
the se. structure of haloperidol and the table below, identify all of the acidic and
unmodified
basic functional groups present in the structure, provide the normal pKa range for each functional
2. Based on their electronic induction.
group, and identify if each functional group would be primarily ionized or unionized in pH environ-
1. Using
3. the se.the in pH environments of 1.7, 5.5, 6.0, 7.4, and 8.5.
Using
ments=1.7, 5.5, 6.0, 7.4, and 8.5.
2. Based on
Answer their electronic induction.
Answer
3. The
Using
The the in pH
structure of environments
structure haloperidol of 1.7, 5.5,
of haloperidolcontains
contains 6.0,
only
only 7.4,
one
one and functional
basic
basic 8.5.
functional group
groupand
andno
noacidic
acidicfunctional groups.
functional
Answer
groups.
The structure of haloperidol contains only one basic functional group and no acidic functional groups.
Tertiary amine
OH
Tertiary amine N
OH
F N Cl
O
F Cl
O
4. Shown below is a structural analog can enhance the duration of haloperidol.
Tertiary amine Basic 9–11 Ionized Ionized Ionized Ionized Ionized
4. Shown
4. Shownbelow
below is
is aa structural
structural analog
analogcan enhance the Evaluate
of haloperidol. duration ofthe
haloperidol.
structural change and propose an
explanation as to how this structural modification can enhance the duration of haloperidol.
5. Using the table below ionizable functional groups.

Answer
Structural evaluation of this analog reveals that the tertiary hydroxyl group has been converted to a
5. lipid soluble
Using ester.
the table Lipid
below solublefunctional
ionizable esters cangroups.
be administered as either an intramuscular (IM) or subcu-
C
taneous (SC) injection. After injection, the lipid soluble ester dissolves slowly from its initial injection
site into the plasma in a consistent manner over an B extended period of time. Once in the plasma, the
ester is hydrolyzed to release haloperidol. Remember that C esterases are ubiquitous within the body
and that lipid and water soluble esters are frequently used as prodrugs D to provide a variety of thera-
A B
peutic advantages.
D
A
2.16 Haloperidol 175
5. Using the table below, identify the types of binding interactions that could be possible between the
boxed functional groups and a protein or enzyme receptor. Also identify amino acids present within
5. Usingorthe
a receptor table below
enzyme whoseionizable functional
side chains could groups.
participate in the interactions that you identified.
Assume a plasma pH=7.4 for all ionizable functional groups.
C
B
D
A
Answer
Amino Acids Capable of Forming
Functional Group Types of Binding Interactions Specific Binding Interaction
A Ketone (1) Ion–Dipole (as the Dipole) (1) Asp, Glu (with carbon of ketone); Arg, Lys,
His* (with oxygen of ketone)
(2) Dipole–Dipole (2) Ser, Thr, Tyr, Cys, Asn, Gln, His*
(3) Hydrogen Bond (Acceptor) (3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His*
B Tertiary amine (1) Ionic (1) Asp, Gln
(2) Ion–Dipole (as the Ion) (2) Ser, Thr, Tyr, Cys, Asn, Gln
C Tertiary hydroxyl (1) Ion–Dipole (as the Dipole) (1) Asp, Glu (with hydrogen of hydroxyl); Arg, Lys,
His* (with oxygen of hydroxyl)
(2) Dipole–Dipole (2) Ser, Thr, Tyr, Cys, Asn, Gln, His*
(3) Hydrogen Bond (Donor and/or Acceptor) (3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His*
D Phenyl ring; aromatic ring; van der Waals; Hydrophobic Tyr, Phe, Trp (better interaction**); Val, Leu, Ile,
aromatic hydrocarbon Met, Ala
*The side chain of histidine is primarily unionized at a pH=7.4. The small fraction that is ionized could
form an ion–dipole interaction with a partially negative atom, while the unionized fraction can serve
as a hydrogen bond donor or acceptor. Additionally, it can serve as the dipole in an ion–dipole inter-
action.
**Stronger van der Waals interactions occur when aromatic rings interact with aromatic rings;
however, all of the listed amino acids could possibly interact with the indicated functional group.
6. Shown below is the structure of haloperidol and a list of five metabolic transformations. For each
metabolic transformation, indicate if it is a phase I or a phase II transformation and if haloperidol has
a functional group present to participate in the transformation. If you answer YES, then draw the
appropriate metabolite; if you answer NO, then provide a brief explanation as to why this metabolic
6. Shown below is the to perform with haloperidol.
transformation is not possible to perform with haloperidol.
Metabolic Pathways
A. Reduction
B. Sulfate Conjugation
C. Hydrolysis
D. Oxidative N-Dealkylation
Answer
A. Reduction: Phase I, Yes
Answer
A. Reduction:
Answer Phase I, Yes
Answer
B. Sulfate conjugation is a phase II transformation. It is possible; however, due to steric hindrance,

B. Sulfate conjugation is a phase II ation is low.
the probability of this metabolic transformation is low.
B. Sulfate conjugation is a phase II ation is low.
C. Hydrolysis is a phase I transformation. It is not possible for haloperidol because its structure does
not contain
C. Hydrolysis a functional
phase group that undergoes this type of transformation.
I biotransformation.
is aN-Dealkylation:
D. Oxidative Phase I, Yes
D. Oxidative N-Dealkylation: Phase I, Yes
C. Hydrolysis is a phase I biotransformation.
E. Benzylic oxidation is a phase I transformation. It is not possible for haloperidol because one
benzylic position is occupied by a ketone (and therefore is not capable of being oxidized) and the
other is directly attached to a heteroatom and lacks a hydrogen atom.
Answers
2.17 Hydrocortisone
Hydrocortisone is a glucocorticoid used in the management of inflammation. Derivatives of hydrocortisone are used
in the management of asthma and chronic obstructive pulmonary disease.
1.17 and 2.17

1. Conduct a complete structural evaluation – remove boldand
of hydrocortisone fromuse
label
the information in the grid to inform
C
F
B
A D
Hydrocortisone
Answer
Function
Function Amino Acids That
Character
Interaction(s) Can Interact with
Acidic, Basic, the Functional
Function 21 Possible with
Character or Neutral Group via Ion–
Biological
Name of Hydrophilic Provide 17
11 ↑ Solubility Target Dipole Interactions
Group Hydrophobic Relevant
A ↑ Absorption pH=7.4 None Is Acceptable
A Ketone Hydrophilic (CO) Neutral Solubility (CO) H-bonding (A) Lys, Arg, Glu, Asp
dipole)
B Cycloalkene Hydrophobic 1.18Neutral

and 2.18 – remove bold fromHydrophobic
Absorption label None
van der Waals
C Secondary Hydrophilic (OH) Neutral Solubility (OH) H-bonding (A+D) Lys, Arg, Glu, Asp
alcohol E
I O
D Ion–dipole
A C (as the
HO I dipole)
OH
N H2
I O
B177 I

D Cycloalkane Hydrophobic Neutral Absorption Hydrophobic None
van der Waals
E Primary alcohol Hydrophilic (OH) Neutral Solubility (OH) H-bonding (A+D) Lys, Arg, Glu, Asp
dipole)
F Tertiary alcohol Hydrophilic (OH) Neutral Solubility (OH) H-bonding (A+D) Lys, Arg, Glu, Asp
dipole)
2. The glucocorticoids interact with residues within the glucocorticoid receptor (Arg611, Asn564, Thr739,
Gln642, and Gln570) via hydrogen bonding and ion–dipole interactions at physiological pH (7.4). Iden-
tify which functional groups could interact with the side chains of these amino acids.
Answer
Can Interact with Can Interact with

Asparagine564 and Glutamine642 and
Threonine739 via a Glutamine570 via a
Can Interact with Arginine611 Hydrogen Bonding Hydrogen Bonding
via an Ion–Dipole Interaction Interaction Interaction
Functional
A Yes Yes Yes
B No No No
C Yes Yes E Yes
D No No No
E Yes C
Yes Yes
F Yes Yes Yes
F
B
3. Several of the functional groups identified in the structure evaluation grid are essential for biological
A transformations that
activity. There are several metabolic D render the glucocorticoids inactive. These
transformations include the following:
1. Ring A ketone reduction Hydrocortisone
2. Ring A double bond reduction
3. C-17 oxidation Question #3 structure needs to be replaced:
4. C-11 oxidation
21
11 17

Based on this information, consider the array of products drawn in the scheme below. Identify each
type of reaction or transformation that has occurred and evaluate each of the products to determine
if each product is active or inactive.
A
B
F 21
11 17
C
A
Answer
Pathway Type of Reaction or Transformation Active or Inactive

A Allylic oxidation followed by dehydration Active
B C-11 oxidation Inactive
C C-17 oxidation Inactive
D C-21 esterification (acetylation) Active
E A ring double bond reduction Inactive
F A ring ketone reduction Inactive
4. The synthetic glucocorticoids are often esterified at C-21 to produce prodrugs. Both lipophilic and
water4.soluble esters cann be
The synthetic formed.
overall drug Evaluate each of the four prodrugs drawn below and determine
water solubility.
whether a lipophilic or water soluble ester is present. Determine how prodrug formation has an
effect on overall drug water solubility.
A B
C D
Answer
Type of Ester Formed Effect on Overall Drug Water Solubility

A Lipophilic ester Decreases overall water solubility of the drug
B Water soluble ester salt Increases overall water solubility of the drug
C Lipophilic ester Decreases overall water solubility of the drug
D Water soluble ester salt Increases overall water solubility of the drug
a. Provide a structural rationale for why prodrugs (e.g., B and D) are used in the preparation of
aqueous injectable products to be administered intramuscularly (IM) or intravenously (IV).
Answer
Drugs that are formulated as aqueous injectable products must be highly hydrophilic in character.
Hydrocortisone contains four hydrophilic functional groups (ketone, primary alcohol, secondary
alcohol, and tertiary alcohol); however, it is not particularly soluble in water. By forming a water
soluble ester salt with the primary alcohol at C-21, an ionizable functional group is introduced.
In the case of prodrug B, the ionizable carboxylic acid is able to interact with water through ion–
dipole interactions and, therefore, significantly increase the overall water solubility of the drug
molecule.
b. Provide a structural rationale for why prodrugs (e.g., A and C) are used in the preparation of
depot injections.
Answer
Drugs that are formulated as depot injections must be highly hydrophobic in character. Hydrocor-
tisone contains a steroid backbone (all four rings) that is highly hydrophobic; however, it still has
some limited solubility in water. By forming a lipophilic ester with the primary alcohol at C-21,
the overall water solubility of the drug decreases substantially. In this case, one of the hydrophilic
groups is now masked as an ester, thereby significantly decreasing its hydrophilic character. As a
lipophilic prodrug, hydrocortisone can be formulated as a suspension for intramuscular or subcu-
taneous injection.
5. Lipophilic glucocorticoid esters typically do not concentrate in the urine, but rather undergo glomer-
ular filtration followed by tubular reabsorption. Provide a brief rationale for why lipophilic glucocor-
ticoid esters do not concentrate in the urine and determine what effect this has on duration of drug
action.
Answer
For drugs to concentrate in the urine, they need to be highly water soluble (contain functional
groups with a significant amount of hydrophilic character). We have already evaluated the overall
water solubility of hydrocortisone to be relatively poor, despite the presence of several hydrophilic
functional groups. The addition of a lipophilic ester will further decrease the water solubility of
the resulting glucocorticoid ester. Because the glucocorticoid ester suffers from poor water solu-
bility, it is not unexpected that it does not concentrate in the urine. These lipophilic esters, however,
have sufficient hydrophobic character to undergo reabsorption in the renal tubules. Because the
drug is returned to systemic circulation via this route of absorption, the duration of drug action is
prolonged.
6. Which type of prodrug, water soluble ester salts, or lipophilic esters, would you anticipate to have
greater systemic side effects?
Answer
The more water soluble the prodrug is, the wider the systemic distribution. The greater the prodrug’s
solubility in the blood, then the greater the potential is for more misadventures/side effects. Because
the water soluble ester salts are by far more water soluble than the lipophilic esters, one would
predict that the water soluble ester salts would exhibit more systemic side effects.
C
F
B
Section
A 4 Whole
D Molecule Drug Evaluation
Answers
Hydrocortisone

2.18 Levothyroxine (T4)
21
11 17
Levothyroxine (T4) is a naturally produced thyroid pro-hormone. In its active form, tri-iodo-L-thyronine (T3) is
responsible for regulating oxygen consumption and calorigenesis (think metabolism, metabolic rate, and thermogen-
esis). T4 is biosynthesized and stored in thyroglobulin
A molecules until it is needed. Once proteolyzed from thyroglob-
ulin and transported to the desired target tissue, T4 undergoes dehalogenation catalyzed by thyroxine dehalogenase to
the active thyroid hormone T3.
1.18
1. Conduct a structural evaluation of and 2.18 – remove
levothyroxine (T4), bold from on
focusing label
the boxed functional groups, and use
the information in the grid to inform your answers to the questions that follow.
E
I D O
A C
HO I
OH
N H2
I O
B I
L-Thyroxine
Answer
Function
Character Amino Acids That

Function
Can Interact with the
Acidic, Basic,
Interaction(s) Functional Group via
Name of Hydrophilic Provide ↑ Solubility Biological Target Interactions at
Functional and/or pKa When and/or at Physiological pH=7.4
A Phenol Hydrophilic (OH) Acidic Solubility (OH) H-bonding (A+D) Ser, Thr, Tyr, Cys, Asn, Gln,
Hydrophobic (Ar) pKa=9–10 Absorption (Ar) Dipole–dipole Trp, His
dipole)
B Ether Hydrophilic (O) Neutral Solubility (O) H-bonding (A) Ser, Thr, Tyr, Cys, Asn, Gln,
dipole)
183

1.18 and 2.18
C – Halogenated
remove bold from label
Hydrophobic Neutral Absorption Dipole–dipole None
aromatic hydro- Ion–dipole (as the
carbon dipole)
Hydrophobic
van der Waals
π-π Stacking
D Primary amine Hydrophilic (NH2) Basic Solubility (NH2) Ion–dipole (as the ion) None
Hydrophobic (R) pKa=9–11 Absorption (R) Ionic
E Carboxylic acid Hydrophilic (CO2H) Acidic Solubility (CO2H) Ion–dipole (as the ion) None
Tri-iodothyronine Hydrophobic (R) pKa=2–5 Absorption (R) Ionic
1. Conduct a structural your answers to the questions that follow.

2. Hormone replacement therapy in the form of levothyroxine (T4) is available for those patients who
1.18 and 2.18 – remove bold from label E supply of T4. Evaluate the structure of levothyroxine and
do not produce an adequate endogenous
determine if it is an enantiomer,Ddiastereomer, or geometric isomer.
A C
O
I O
H 2N
OH HO I
H OH
B H NH
2
I O
OH L-Thyroxine I please change caption to Levothyroxine>
<DAVID:
Hormone replacement, diastereomer, or geometric isomer.

2.Answer
Evaluation of the structure of levothyroxine reveals that there is one chiral carbon atom. Because
there is only one chiral carbon atom, levothyroxine represents an enantiomer. Diastereomers require
the presence of at least two chiral carbon atoms so levothyroxine does not represent a diastereomer.
Further inspection of the molecule reveals that there are no carbon–carbon double bonds or other
conformationally restricted functional groups so geometric isomers are not possible.
3. Evaluate the chiral carbon atom in levothyroxine to determine if this drug is drawn as the R- or
S-enantiomer. Levothyroxine
Answer
Using the Cahn-Ingold-Prelog (CIP) system (see Chapter 7 in Basic Concepts in Medicinal Chemistry),
3.theEvaluate the chiral
four groups carbon
attached to atom this drug
the chiral is drawn
carbon as the R- orbased
are prioritized S-enantiomer.
on atomic number and the
described sequence rules. Using these rules, the primary amine nitrogen atom is prioritized as #1, the
Answer:
carboxylic acid #2, the methylene unit attached to the aromatic hydrocarbon has the #3 priority, and
the hydrogen atom pointing away from the reader is the #4 priority. This assessment provides the
Using the; therefore, the S-enantiomer is drawn.
evidence for the prioritization scheme indicated below. In reviewing the positions of these priorities
it is noted that they are counterclockwise in orientation; therefore, the S-enantiomer is drawn.
3 2
4 1
2.18 Levothyroxine (T4) 185
4. T3 is the biologically active hormone. It interacts with the thyroid hormone receptor via hydrogen
4. T3 is the biologically identified in hydrophobic,
bonding, ion–dipole, the structure evaluation
and ionic grid.
interactions. Evaluate the ribbon diagram that shows
how T3 interacts with the surface of the thyroid receptor and identify the types of interactions
possible for each of the five functional groups identified in the structure evaluation grid.
I O
HO I
OH
H N H2
O
I
Tri-iodo-L-thyronine
Tri-iodothyronine
Answer
A. 1.18 and 2.18
Phenol: – removevia
OH interacts bold from labelas the H-bond donor.
H-bonding
5. T4 is biosynthesized
NOTE: from L-tyrosine
The phenol OHwithin derived
is capable of from L-tryosine.as a H-bond donor and acceptor. In this case the
participating
phenol specifically
O interacts with the thyroid receptor as the H-bond donor.
B. H O
Ether: no role in binding interaction. I O
2N I O
H 2 NC. Halogenated OH HO I
HOH aromatic H hydrocarbon:
O halogens
I interact via hydrophobic interaction;
OH aromatic
H hydrocarbon interacts via hydrophobic interactions or π-π stacking. OH
H NH
2
D. Primary amine: no role in binding interaction. I HO N H
2
I O
OH
E. Carboxylic acid: participates in ion–dipole (as the ion) or ionic I interactions.
OH I
L-Tyrosine Tri-iodothyronineLevothyroxine
5. T4 is biosynthesized from L-tyrosine within the thyroglobulin molecule and is considered an amino
acid–based hormone. Other hormones In the body are steroid-based (e.g., estrogen) or peptide-
Answer: based (e.g.,1.18 and 2.18
insulin). – remove
Evaluate bold from of
the structure label
T4 and justify its classification as an amino acid–based
hormone by determining which functional groups are derived from L-tyrosine.
The biosynthesis s found in the amino acid tyrosine.
O
I O
H 2N
OH HO I
H OH
A I B O H NH
2
HO I I O
OH OH
I
NH2
I
L-Tyrosine O Levothyroxine
I
Answer
Levothyroxine
The biosynthesis of levothyroxine occurs within the thyroglobulin molecule which is rich in L-tyrosine
residues. Iodination of the tyrosine units and phenolic coupling represent some of the biochemical
reactions that occur in the biosynthesis of the natural hormone. Box A is derived from L-tyrosine, as is
Answer: I
HO I
evident
Thebybiosynthesis
the presence of only
s found in the phenolacid
the amino portion of the amino acid side chain. Box B is also derived
tyrosine.
from L-tyrosine; however, the phenol has become an ether. The rest of the boxed atoms represent
each of the atoms found in the amino acid tyrosine. O
I
A I I
B O O A
HO HO I I
OH OH
NH2 H NH
I I O O
2
I
I I HO I
Levothyroxine
Levothyroxine
Levothyroxine
I O
6. Interestingly, the dehalogenation transformation represents both an activation and deactivation

pathway for T4. The iodo substituents on the inner ring of T4 play a role not only in important hydro- B
phobic binding interactions with the receptor, but also in maintaining the shape of the hormone in
a perpendicular orientation (see diagram below). This perpendicular shape is necessary to appro-
priately position the phenolic OH to participate in key receptor binding interactions. Evaluate the
metabolites produced from the dehalogenation transformations and identify which metabolite is
active and which is not. Provide a brief rationale for your answers.
I O
I
HO
OH
H NH
A O
2
C
I
I O D A
HO I
OH
H NH
2
B
I O I O
I Lidocaine HO I
OH
Levothyroxine H NH
2
I O
2.18 Levothyroxine (T4) 187
Answer
• Evaluation of the dehalogenation transformation that leads to metabolite A: The outer ring of
levothyroxine is dehalogenated to produce metabolite A. This metabolite retains the two inner
ring iodo substituents; therefore, the shape of the hormone remains perpendicular. This metabo-
lite retains its biological activity.
• Evaluation of the dehalogenation transformation that leads to metabolite B: The inner ring of
levothyroxine is dehalogenated to produce metabolite B. This metabolite retains only one inner
ring iodo substituent; therefore, the shape of the hormone cannot remain perpendicular. Because
the phenol is not positioned appropriately to participate in an important binding interaction
with the thyroid hormone receptor, this metabolite is inactive.
Answers
2.19 Lidocaine
As a sodium channel blocker lidocaine has found therapeutic use both as a local anesthetic and as a Class IB antiarrhythmic
agent. As an anesthetic, this agent demonstrates rapid onset of action (acts quickly) and a longer duration of action
(lasts longer) than most amino ester-type local anesthetics. The most frequently observed side effects are changes in
the central nervous system (CNS) (e.g., dizziness, lightheadedness, and tinnitus). Lidocaine is extensively metabolized
by the CYP1A2 isozymes to a variety of metabolites.
1. Conduct a the in the grid to inform your answers to some of the questions that follow.
1. Conduct a complete structural evaluation of lidocaine, place your answers in the grid provided, and then
use the evaluation information in the grid to inform your answers to some of the questions that follow.
C H3 CH3
O
N C H3
N
C H3 H
Lidocaine
Lidocaine
Answer
Answer:
Function
Character
Amino Acids That
Acidic, Function Can Interact with the
A
Basic, Functional Group via
Character C
Function
Interaction(s)
or Neutral Possible with Hydrogen Bonding
Interactions at
Name of Hydrophilic Provide ↑ Solubility D
Biological Target
pH=7.4
Functional and/or pKa When and/or at Physiological
A Aromatic Hydrophobic Neutral Absorption Hydrophobic None
hydrocarbon B
van der Waals
π-π Stacking
Lidocaine
B Amide Hydrophobic (R) Neutral Absorption (R) H-bonding (A + D) Ser, Tyr, Thr, Cys, Asn, Glu,
Hydrophilic (CON) Solubility (CON) Dipole–dipole His, Trp,
2. Based on the information in the dipole)
3. Local anesthetics that have.
189
C H3 CH3
O
N C H3
190 Medicinal Chemistry Self Assessment N
C H3 H
C Tertiary amine Hydrophobic (R) Basic Absorption (R) Ion–dipole (as the None
Hydrophilic (N) pKa 9–11Lidocaine
Solubility (N) ion)
Ionic
Answer:
D Aliphatic alkane Hydrophobic Neutral Absorption Hydrophobic None
van der Waals
A
C
Lidocaine
Lidocaine
2. Based on the information in the structure evaluation grid, determine whether or not lidocaine is
likely
2.soluble
Basedinonthe
theblood (pH=7.4).
information in the
Answer
3. Local anesthetics that have.
Lidocaine contains functional groups that contribute to the overall hydrophobic character of the
molecule (e.g., aromatic hydrocarbon and aliphatic alkanes), as well as functional groups that
contribute to the overall hydrophilic character of the molecule (e.g., amide and tertiary amine). The
hydrophilic character of the molecule enhances its water solubility, whereas the hydrophobic char-
acter enhances its ability to be absorbed across lipophilic membranes. At pH=7.4, the tertiary amine
will be predominantly in its ionized form which will further increase the water solubility of the drug.
The possibility of H-bonding interactions between the amide and water and an ion–dipole interaction
between the tertiary amine and water suggests that lidocaine is likely soluble in the blood.
3. Local anesthetics that have a rapid onset of action are rapidly distributed in the body and can be
absorbed easily across lipophilic membranes. Based on the information in the structure evaluation
grid, provide a rationale for why lidocaine is rapidly distributed and can easily be absorbed across
lipophilic membranes.
Answer
Based on the information in the structure evaluation grid, we know that lidocaine is likely soluble in
the blood due to the presence of hydrophilic functional groups (amide and ionizable tertiary amine).
If the drug is soluble in the blood, then it can be readily distributed in the body.
Based on the information in the structure evaluation grid, we also know that lidocaine is composed
of functional groups with a fair amount of hydrophobic character (aromatic hydrocarbon, aliphatic
alkanes). This will enhance absorption across lipophilic membranes. Rapid distribution and absorption
across lipophilic membranes contributes to the ability of lidocaine to have a rapid onset of action.
2.19 Lidocaine 191
4. Unless excreted unchanged, drug molecules undergo one or more metabolic transformations to
deactivate the drug and/or make the drug sufficiently water soluble to permit elimination. There are
a variety of transformations that are possible for most drugs, but only the minimum number of trans-
1.19 and 2.19actually
formations – remove bold The
occurs. fromfollowing
labels anddiagram
remove captures
answers the
frommetabolic
over the arrows (payfor
pathways nolidocaine
attention to
the colors)
that are observed clinically. For each transformation, identify which phase I metabolic transformation
has taken place next to the relevant arrow.
Answer
C H3 C H3
O
N C H3
N
C H3 H
Lidocaine
C H3 C H3
HO C H3 O H
O
N C H3
N C H3 N
N
C H3 H
C H3 H
Monoethylglycinexylidide
HO C H3
O H
N C H3
N
C H3 H C H3 C H3
O
N H2
3-Hydroxy-monoethylglycineexylidide N H2 N
C H3 C H3 H
+
Glycinexylidide
O H
N C H3
HO
5. Now that you have identified the metabolic transformations that generate products that have been
identified, put your detective hat on and list any additional phase I transformations that could have
occurred.
Answer
Benzylic oxidation (on either or both of the aromatic ring methyl substituents). The resulting primary
alcohol can subsequently undergo alcohol oxidation to the corresponding aldehyde. The aldehyde
then undergoes aldehyde oxidation to the corresponding carboxylic acid.
6. Lidocaine suffers from CNS-based toxicities largely due to production of the N-dealkylated metabolic
product monoethylglycinexylidide once the parent drug has crossed the blood–brain barrier.
a. Provide a structural rationale for why lidocaine is able to cross the blood–brain barrier.
Answer
Based on the information in the structure evaluation grid, we know that lidocaine has a fair
amount of hydrophobic character (aromatic hydrocarbons with aliphatic substituents, aliphatic
alkane substituents on amine) that enhance absorption across lipophilic membranes. At pH=7.4,
the tertiary amine will be predominantly ionized. Because an equilibrium between the ionized
and unionized forms of lidocaine exists, a very small percentage of the drug will be in its union-
ized form at any given time. The blood–brain barrier is highly selective. To cross this membrane
via passive diffusion, drugs typically must be in their unionized form and be highly lipophilic.
Because of the presence of the ionizable amine, only very small amounts of lidocaine will cross
the blood–brain barrier and then undergo oxidative N-dealkylation to produce an N-dealkylated
metabolic byproduct—monoethylglycinexylidide, the cause of the CNS-based toxicity observed.
b. Interestingly, neither
1.19 and 2.19 tocainide
– remove nor
boldtolycaine
from labeldemonstrates similar CNS-based toxicities. Provide a
structural rationale for why these two local anesthetics are devoid of CNS-based side effects.
Tolycaine Tolcainide
Answer
1.25 and 2.25
From a structural – remove
perspective bold from
tolycaine is label
structurally identical to lidocaine with the exception
of the presence of a methyl ester instead of a benzylic methyl group. This methyl ester readily
A catalyzed ester hydrolysis, a phase I metabolic transformation, to the corresponding
undergoes enzyme
carboxylic acid. The resulting metabolic product will be ionized at physiological pH via two
B
functional groups, the carboxylic Cacid and the tertiary amine. Even though tolycaine can undergo
oxidative N-dealkylation to produce an N-dealkylated product that closely resembles mono-
ethylglycinexylidide, it is highly unlikely thatDthis drug will cross the blood–brain barrier due to
the presence of these two ionizable functional groups. Again, although an equilibrium exists
between the ionized and unionized forms of both the carboxylic acid and the tertiary amine
functional groups, there is only a very small fraction of the drug that is completely unionized at
any point in time.
Tocainide contains severalSitagliptin
of the same functional groups found in lidocaine, but does not contain
an alkylated amine. The hydrophobic character afforded by the substituted aromatic hydro-
carbon and the presence of an amine-substituted aliphatic alkane will certainly contribute to the
ability of2.25
the–drug
remove bold the
to cross fromblood–brain
label barrier. The primary amine will also be predominantly
ionized at pH=7.4 and, therefore, only a fraction of the time will it be available in its unionized
form. These structural characteristics are similar to lidocaine so it is possible for tocainide to cross
the blood–brain barrier. Unlike lidocaine, tocainide cannot undergo oxidative N-dealkylation, and
the metabolic byproducts that cause CNS-based toxicity are not formed.
Answers
2.20 Montelukast and Zafirlukast
Shown below are the structures of montelukast and zafirlukast. These drug molecules are administered orally for the
treatment of asthma and allergic rhinitis.
Montelukast
Zafirlukast
1. The structure of montelukast contains one acidic functional group (pKa=4.4) and one basic functional
group (pKa=3.1), whereas the structure of zafirlukast only contains one acidic functional group (pKa=4.3).
1. The structure of a solution pH of 8.3.
Identify these acidic and basic functional groups and predict whether they will be primarily ionized or
primarilyAnswer:
unionized at a stomach pH=1.9, a urine pH=5.4, a cellular pH=6.1, a plasma pH=7.2, and a solu-
tion pH=8.3.
Carboxylic acid
Acidic (pKa = 4.4)
Sulfonamide
Acidic (pKa = 4.3)
Montelukast
Aromatic heterocylic amine

Basic (pKa = 3.1)
193
Zafirlukast
1. The structure of a solution pH of 8.3.
Answer:
Answer
Carboxylic acid
Acidic (pKa = 4.4)
Sulfonamide
Acidic (pKa = 4.3)
Montelukast
Aromatic heterocylic amine

Basic (pKa = 3.1)
Zafirlukast

Functional Group Basic 1.9 5.4 6.1 7.2 8.3
Carboxylic Acid Acidic Unionized Ionized Ionized Ionized Ionized
2. In the previous question, we to calculate the percent of the functional group that would be ionized.
3. The
Aromatic sodium saltBasic
heterocyclic an explanation for this difference.
Ionized Unionized Unionized Unionized Unionized
amine
Sulfonamide Acidic Unionized Ionized Ionized Ionized Ionized
2. In the previous question, we examined three pKa values in five different environments for a total of
15 different scenarios. Which of these 15 scenarios allow you to use the Rule of Nines to calculate
scenarios and use the Rule of Nines to calculate the percent of the functional group that would be
ionized.
Answer
To use the Rule of Nines, the difference between the pH and the pKa must be an integer (i.e., 1, 2, 3).
In evaluating the above 15 scenarios, there are three scenarios that meet this criterion, the carbox-
ylic acid of montelukast (pKa=4.4) at a urine pH=5.4, the aromatic heterocyclic amine of montelukast
(pKa=3.1) at a cellular pH=6.1, and the sulfonamide of zafirlukast (pKa=4.3) at a solution pH=8.3. For
the carboxylic acid of montelukast, |pH – pKa| is equal to 1; thus, there is a 90:10 ratio. Because the
carboxylic acid (pKa=4.4) would be primarily ionized in a basic environment (pH=5.4), we can use this
ratio to determine that it would be 90% ionized. For the aromatic heterocyclic amine of montelu-
kast, |pH – pKa| is equal to 3; thus, there is a 99.9:0.1 ratio. Because the aromatic heterocyclic amine
(pKa=3.1) is a basic functional group, it would be primarily unionized in a basic environment (pH=6.1).
We can use this information to predict that it would be 0.1% ionized. For the sulfonamide of zafirlu-
kast, |pH – pKa| is equal to 4; therefore, there is a 99.99:0.01 ratio. Because the sulfonamide (pKa=4.3)
is an acidic functional group, it would be primarily ionized in a basic environment (pH=8.3). Thus, we
can use this information to predict that it would be 99.99% ionized.
2.20 Montelukast and Zafirlukast 195
3. The sodium salt of montelukast is required for its oral administration, whereas zafirlukast can be
administered orally as its unionized free acid form. Conduct a structural analysis of these two drug
molecules and provide an explanation for this difference.
Answer
A sodium salt is an inorganic salt of the parent drug. The primary purpose of using an inorganic
salt is to enhance the water solubility of a drug molecule. This in turn enhances its solvation and
dissolution with the aqueous environment of the gastrointestinal (GI) tract. Since montelukast must
be administered as an inorganic salt, whereas zafirlukast does not have this requirement, this indi-
cates that zafirlukast has higher water solubility than montelukast. In evaluating their structures, it
is found montelukast and zafirlukast each contain three water soluble functional groups, and the
remainder of their structures is comprised of alkyl chains, aromatic rings, a thioether, and a halogen.
All of these latter functional groups bestow lipid solubility to their respective drug molecules. A
key difference between these two structures is the overall nature of their water soluble functional
groups. The sulfonamide of zafirlukast has a wider charge distribution (four atoms) than does the
carboxylic acid of montelukast (two atoms; Comparison A). Additionally, the carbamate group of
zafirlukast has the ability to form more hydrogen bonds with water than does the tertiary hydroxyl
group of montelukast (Comparison B). The ability to act as hydrogen bond acceptors would be
expected to be similar for the methoxy group of zafirlukast and the aromatic heterocyclic amine of
Answer:
montelukast (Comparison C). Please note that the nitrogen atom of the indole ring is an extremely
weak base (pK
A sodium salt isa <
an0.1)
ilityand
o thecannot
indole participate
ring. in hydrogen bonds. This is because the lone pair of elec-
trons on the nitrogen atom are required for the aromaticity of the indole ring.
–
A O O
B
OH
S H3C C H3
Cl N
C C A
H3 CO O C H3
Montelukast O
B
–
N S
H
O N O
O
N Zafirlukast
C H3
In addition, the overall lipid soluble character of montelukast is greater than that of zafirlukast.
The structure of montelukast contains 34 aromatic or aliphatic carbon atoms (as well as a halogen
4. atom), whereas
Montelukast and.the structure
Assume that of
all zafirlukast containsoccur
binding interactions only 28
at aatoms. The combination
physiological pH of 7.4. of a lower water
soluble nature and a higher lipid soluble nature is responsible for the need to utilize a sodium salt for
Answer:
the oral administration of montelukast.
Let us four nd hydrophobic interactions.
The four boxed areas could interact with a Ionic bond

hydrophobic pocket within the leukotriene receptors.
Hydrogen bond
(as acceptor)
S H3C C H3
Cl N
C C A
H3 CO O C H3
4. Montelukast and Montelukast O
zafirlukast exert their mechanism ofBaction by interacting with cysteinyl leukotriene
receptors and blocking the normal actions of endogenous leukotrienes (LTC4, LTD4, and NLTE – ). It has
S
4
been proposed that this interaction requires five key elements:
H an ionic interaction, a hydrogen bond
O as N
interaction where the antagonist acts as the acceptor, O
well as the interaction of the antagonist
with three separate hydrophobic pockets within the receptor. Using this information and the struc-
O binding interactions between these drug
tures of montelukast and zafirlukast, propose potential N Zafirlukast
molecules and cysteinyl leukotriene receptors. Assume that all binding interactions occur at a physi-
ological pH=7.4. C H3
Answer
Let us evaluate these two drug molecules separately. The structure of montelukast contains a carbox-
4. ylic acid that could
Montelukast participate
and. Assume that in
allan ionic interactions
binding bond with the leukotriene
occur receptors.
at a physiological pH It
of also
7.4. contains two
functional groups, the tertiary hydroxyl group and the aromatic heterocyclic amine, that could
Answer: in a hydrogen bonding interaction as an acceptor. As shown below, the structure of
participate
montelukast contains
Let us four nd four separate
hydrophobic regions that could interact with the three hydrophobic pockets
interactions.
of the receptor via van der Waals and hydrophobic interactions.
The four boxed areas could interact with a Ionic bond

hydrophobic pocket within the leukotriene receptors.
Hydrogen bond
(as acceptor)
Hydrogen bond
(as acceptor) Montelukast
Similarly, the structure of zafirlukast contains a sulfonamide group that could participate in an ionic
interaction with the leukotriene receptor, as well as two functional groups, the methoxy group and
the carbamate, that could participate in a hydrogen bonding interaction as an acceptor. As shown
below, the structure
Similarly, of zafirlukast
the structure of groupalso
that contains four separate
could participate regions
in an ionic bondthat
withcould interact with the
the leukotriene.
three hydrophobic pockets within the receptor.
Hydrogen bond
(as acceptor)
The four boxed areas could interact with a
hydrophobic pocket on the leukotriene receptors.
Ionic bond
Hydrogen bond Zafirlukast

(as acceptor)
5. Calculated log P values of montelukast or be primarily excreted unchanged?
6. Shown below is the to perform with zafirlukast.

2.20 Montelukast and Zafirlukast 197
5. Calculated log P values of montelukast and zafirlukast lie in the range of 5.5 to 6.4 depending on the
computer program used to predict these values. Given this information, would these drug molecules
be predicted to be highly plasma protein bound or minimally plasma protein bound? Additionally,
would you expect these drug molecules to undergo extensive hepatic metabolism or be primarily
excreted unchanged?
Similarly, the structure of group that could participate in an ionic bond with the leukotriene.
Answer
Plasma proteins are used by the human body to transport endogenous molecules
Hydrogen bondin the plasma from
one cell to another. Given that the plasma is water soluble, these proteins are primarily required to
(as acceptor)
carry those endogenous molecules that have a high level of lipid solubility (e.g., estradiol, choles-
The four boxedThis
terol, hydrocortisone). areas could
is also interact
true with a
for exogenously administered drug molecules. Drug molecules
hydrophobic pocket on the leukotriene receptors.
that have a more lipid soluble character have a greater affinity for plasma proteins than do those
that have a more water soluble character. Thus, using the calculated log P values provided for monte-
lukast and zafirlukast, it would be expected that these two drug molecules would be highly plasma
protein bound.
The primary purpose of drug metabolism is to enhance the removal of the drug molecule from the
Ionic and
human body. Drug molecules that already possess adequate water solubility, bondthus can be readily
eliminated, generally undergo minimal or no metabolism, whereas drug molecules that are highly
lipid soluble often undergo extensive metabolic transformation. Thus, using the calculated log P
values provided for montelukast and zafirlukast, it would be expected that these two drug molecules
would undergo extensive hepaticHydrogen bond
metabolism. Zafirlukast
(as acceptor)
6. Shown below is the structure of zafirlukast and a list of five metabolic transformations. For each
metabolic transformation,
5. Calculated log P valuesindicate if it is aorphase
of montelukast I or a phase
be primarily II transformation
excreted unchanged? and if zafirlukast has
a functional group present to participate in the transformation. If you answer YES, then draw the
appropriate metabolite; if you answer NO, then provide a brief explanation as to why this metabolic
transformation
6. Shown below is not possible
is the to perform
to perform with zafirlukast.
with zafirlukast.
Metabolic Pathways
A. Methylation
B. Aromatic Oxidation
C. Hydrolysis
D. Oxidative O-Dealkylation
ReplacementStructuresforBatch3
Chapter2.20
Answer
Pleasereplacethestructureforanswer6B(page5)withtheoneshownbelow.
A. Methylation: No. Methylation is a phase II metabolic transformation that requires a catechol, a
phenol, an amine, or a sulfhydryl functional group. Because none of these functional groups are
Answer:
present within the structure of zafirlukast, this metabolic transformation cannot occur.
B. Aromatic Oxidation: Phase I; Yes
A. Methylation: No., this metabolic transformation cannot occur.
B. Aromatic Oxidation: Phase I; Yes
Note: Aromaric hydroxylation

could also occur on these
rings; however, they are
more sterically hindered.
Note: Aromaric hydroxylation
could also occur on this
ring; however, it is more

Pleasereplacethestructureforanswer6C(page6)withtheoneshownbelow.
C. Hydrolysis: Phase I; Yes
H3 CO O C H3
O
OH
N S
H H
HO N O
Pleasereplacethestructureforanswer6D(page6)withtheoneshownbelow.
O Note: It is also possible to
N hydrolyze the sulfonamide.
C H3
Pleasereplacethestructureforanswer6D(page6)withtheoneshownbelow.
O
D. Oxidative O-Dealkylation: Phase I;
O Yes C H3
H HO H
O
O Oxidative O-dealkylation
N S
H H of methoxy functional group
O N HO OO C H3
H H
O
O Oxidative O-dealkylation
N N S
H H of methoxy functional group
O N C H3 O
O
N
C H3
O
H3 CO O C H3
O
N S Oxidative O-dealkylation
O H H
OO C H3 of carbamate functional group
HO N H3 CO
O
O N S Oxidative O-dealkylation
N
H H of carbamate functional group
HO N C H3 O

O
N
C H3
Pleasereplacethestructureforanswer6E(page6)withtheoneshownbelow.

E. Benzylic Oxidation: Phase I; Yes
Pleasereplacethestructureforanswer6E(page6)withtheoneshownbelow.
Benzylic oxidation can occur at two sites;

however, the one in the middle of the
molecule is more sterically hindered.

Benzylic oxidation can occur at two sites;
however, the one in the middle of the
molecule is more sterically hindered.

Answers
2.21 Phenobarbital and

Other Barbiturates
Shown below are the structures of butabarbital, secobarbital, and phenobarbital. These drug molecules are used as
2.21 Phenobarbital and Other Barbiturates
sedative-hypnotic agents in the treatment of insomnia and to induce sedation prior to surgical procedures. Phenobar-
bital can be used in the treatment of a number of different seizure disorders. Their sedative properties are due to their
ability to interact
Shown below with thestructures
are the GABAA receptor
of buta in the central nervous system (CNS).
O and OtherOBarbiturates
2.21 Phenobarbital O O O O
HN NH HN NH HN NH
Shown below are the structures of buta
O O O
O O O O O O
1. Conduct a structural previously listed.
1. Conduct aHstructural
Answer:
N N H analysis of these drug H N molecules
N H and provide an explanation
HN NHas to why they can be
administered orally for the indications previously listed.
These three drug to their site of action.
Answer O O O
These three drug molecules vary only in the alkyl chains and aromatic rings located at the 5 position of barbi-
turic acid. As shown below, barbituric acid is symmetrical Only and
site contains
of two identical imide functional groups (a
type of β-dicarbonyl). While the pKa range for a β-dicarbonyl variationranges from 4.5–8.5, imides tend to have values
at the upper end of this range. As
1. Conduct a structural previously listed.such, they can be ionized in the small intestine to a limited extent and
participate in hydrogen bonds with water when present in the unionized state. This provides sufficient water
Answer:
solubility for solvation and dissolution. The alkyl chains and aromatic ring provide sufficient lipid solubility to
permit these
These three drug molecules
drug to cross
to their site the gastrointestinal 5mucosal membrane and be orally absorbed. This lipid
of action.
solubility facilitates absorption across the blood–brain barrier to gain access to their site of action.
Imide Imide
Only 1site of 3
variation
Barbituric Acid
5
2. Butabarbital and secobarbital these two administered as their sodium salts.
Imide Imide
Answer: 1 3
Barbituric Acid
199
2. Butabarbital and secobarbital these two administered as their sodium salts.
5
Imide Imide
1 3
Barbituric
2. Butabarbital and secobarbital are marketed as their sodiumAcidsalts and phenobarbital is marketed in its
free acid form (i.e., non-salt form). Draw the sodium salt of either butabarbital or secobarbital and
provide an explanation as to why these two drug molecules need to be administered as their sodium
salts. 2. Butabarbital and secobarbital these two administered as their sodium salts.
AnswerAnswer:
Phenobarbital
Sodium Butabarbital Sodium Secobarbital
(Used as Free Acid)
In general the primary reason that drug molecules are administered in their inorganic salt form is to
3. Using
enhance the information
solvation, in acting
dissolution, agent solubility.
and water (onset of action = 30–60and
Butabarbital minutes; durationneed
secobarbital = 10–16 hours).
to be admin-
istered as their sodium salts, whereas phenobarbital does not. This suggests that butabarbital and
secobarbital have greater lipid solubilities than phenobarbital and therefore need to be administered
in a more water soluble form. The authors do not expect the readers to know the structure-activity
relationship (SAR) of barbiturates, so the following information is offered to show how the logical
application of key concepts often explains known facts. Structural activity studies of barbiturates
have demonstrated that alkyl chains at the 5 position of barbituric acid produce more lipid solubility
than the aromatic ring in the structure of phenobarbital. Phenobarbital has a log P value=1.46, while
butabarbital and secobarbital have log P values=1.60 and 2.36, respectively.
3. Using the information in questions 1 and 2, and your answers to those questions, provide an explanation
as to why secobarbital is a short-acting agent (onset of action = 10–15 minutes; duration = 3–4 hours),
butabarbital is an intermediate-acting agent (onset of action = 45–60 minutes; duration = 6–8 hours), and
phenobarbital is a long-acting agent (onset of action = 30–60 minutes; duration = 10–16 hours).
Answer
As discussed in the previous two questions, these three drug molecules are structurally similar and
vary only in the hydrocarbon chains at position 5 of the barbituric acid ring. These minor structural
variations result in differences in their respective lipid solubilities. Drug molecules that have higher
lipid solubility (log P) traverse more quickly through lipid membranes, but are more likely to undergo
metabolic transformation than drug molecules that have lower lipid solubility. Secobarbital is the
most lipid soluble of the three drug molecules. As such, it is rapidly absorbed, can rapidly cross the
blood–brain barrier, and has the quickest onset of action. Due to its higher lipid solubility, it is metab-
olized quicker than either butabarbital or phenobarbital. This rapid metabolism is responsible for the
relatively short duration of action. Butabarbital and phenobarbital are less lipid soluble than secobar-
bital and have similar onsets of action; however, phenobarbital has a lower lipid solubility, is metabo-
lized at a slower rate, and thus has a longer duration of action than butabarbital.
2.21 Phenobarbital and Other Barbiturates 201
4. Secobarbital contains an ionizable functional group with a pKa=7.9. Using the table shown below,
identify the functional group, provide the normal pKa range for the functional group, and identify if
4. the
Secobarbital
functionalbegroup
primarily
wouldionized or unionized
be primarily at pH
ionized or environments of 1.5,
unionized at pH 5.9, 6.3, 7.4, and5.9,
environments=1.5, 8.9.6.3, 7.4,
and 8.9.
Imide
(Acidic)
Secobarbital
Answer
5. As stated above between secobarbital and the side chains of the amino acids indicated.
Answer:
One that involve
β-Dicarbonyl (Imide) the side chains4.5-8.5
Acidic of valine and phenylalanine.
Unionized Unionized Unionized Unionized Ionized
<Production—Please change hyphens to n dashes for Dipole-Dipole in figure}
5. As stated above, barbiturates exert their mechanism of action by interacting with the GABAA recep-
tors. Assume that the following amino acids are involved in this binding: Val, Phe, Ser, Asn, and Lys.
Using the functional groups present within the structure of secobarbital, identify five specific binding
interactions between O R4 and
Phe secobarbital vanthe
derside
Waals
chains of the amino acids indicated.
N H Hydrophobic Interaction
Answer
R3
One potential response is shown below. Please note that other correct response options are available
for this particular question. The primary amine of lysine will be primarily ionized within a cell. The
imide of secobarbital has a pKa=7.9, so it would be approximately 25% ionized at a pH=7.4. The local
O
environment within a binding site may alter the acidity of this functional group. If this functional
Asn R2
group was not R1 ionized, it could still interact with lysine via an ion–dipole interaction. Asparagine can
participate in both
N dipole–dipole interactions as well as hydrogenR5 vanbonds. The ability to participate in
der Waals
a dipole–dipoleHinteraction is illustrated here to provide examples of different types of interactions.
Hydrophobic Interaction
Dipole-Dipole
The positions of the serine and asparagine could be switched to form different hydrogen bonds. The
O O O O
Interaction
same is true for the van der Waals interactions that H Ninvolve theVal
side chains of valine and phenylala-
N H2
nine. – R6
N N
H
O H3 N
+
H Ionic Bond
R10 N O H
R7
Lys
Hydrogen Bond O
R9 Ser HN O
R8
One that involve the side chains of valine and phenylalanine.
<Production—Please change hyphens to n dashes for Dipole-Dipole in figure}
Phe O R4 van der Waals

NH Hydrophobic Interaction
R3
O
Asn R2
R1
N R5 van der Waals
H Hydrophobic Interaction
Dipole-Dipole
O O O O
Interaction HN
N H2 Val
– R6
N N
H
O +
H3 N
H Ionic Bond
R10 N O H
R7
Lys
Hydrogen Bond O
R9 Ser HN O
R8
Chapters1.21and2.21
6. Shown below are known metabolites of butabarbital, secobarbital, and phenobarbital. Identify the
metabolic transformations that are required to produce each metabolite and indicate if they are
PleasereplacetheindicatedstructureinQuestion6inboth1.21and2.21(theonethatispartofthequestion)
phase I or phase II transformations. Would you expect any of these metabolites to retain their
withtheonebelow.Bothstructureshadanidenticalerror.
pharmacological activity? Why or why not?

butabarbital secobarbital phenobarbital
Answer
• Butabarbarbital: ω oxidation (phase I) followed by glucuronic acid conjugation (phase II)

•
Secobarbital: oxidation of the double bond (water reacts with the initial epoxide to produce a diol) and
ω-1 oxidation; the order of these phase I transformations is unimportant
Chapter2.22
• Phenobarbital: aromatic oxidation (hydroxylation, phase I) followed by sulfate conjugation
(phase II)
Intramolecular
Hydrogen Bond
2.21 Phenobarbital and Other Barbiturates 203
These metabolites would not be expected to retain the pharmacological activity that was present in
the parent drug molecules. For any drug molecule to produce a pharmacological effect, it needs to
contribute complementary interactions with its biological target. The alkyl chains and aromatic ring
are important for forming van der Waals and hydrophobic interactions with hydrophobic amino acids
within the GABAA receptor. The addition of hydrophilic functional groups at this position decreases
their ability to form these key interactions. Furthermore, the addition of these hydrophilic functional
groups in the liver would greatly decrease or eliminate the ability of these metabolites to cross the
blood–brain barrier and reach their site of action in the CNS.
Answers
2.22PravastatinandFluvastatin
ShownShown
belowbelow
are theare
structures of pravastatin
the structures and fluvastatin.
of pravastatin. A total ofThese drug molecules
six functional groups are
haveused in boxed.
been the treatment of
various types of hyperlipidemia/dyslipidemias. A total of six functional groups have been boxed.
F
C
B
D
Pravastatin
Fluvastatin
1. Using the table below, drophilic or hydrophobic in character. for your response.
1. Using2.theThe logbelow,
table P values of s and
identify theprovide a structural
six boxed explanation
functional for the
groups. For difference
each in these log
of the functional P values.
groups you
identify, indicate
Answer if it is hydrophilic or hydrophobic in character. Also provide a brief explanation for your
response.
The log P value is a functional groups than the structure of fluvastatin, it has a lower log P value.
Answer

3',5'-Dihydroxy-
A Alkyl group; alkyl chain; aliphatic chain heptanoic
Hydrophobic due to its inability to ionizeacid
or form hydrogen bonds; hydrocarbon functional
groups enhance lipid solubility
Ester
B Ester Hydrophilic due to its ability to act as a hydrogen bond acceptor
C Secondary hydroxyl (secondary alcohol) Hydrophilic due to its ability to form hydrogen bonds as either a donor or an acceptor
Isobutyl chain
D Halogen; fluorine Effects can vary; fluorine can act as a hydrogen bond acceptor; however, studies have
shown that the substitution of a hydrogen atom with a fluorine atom tends to slightly
enhance lipid solubility
E Aromatic ring system; heterocyclic Hydrophobic due to its inability to ionize or form hydrogen bonds; the lone pair of
aromatic ring; indole electrons present on the nitrogen atom are involved in the aromaticity of the ring system
and therefore are not available to form hydrogen bonds; the remaining hydrocarbons
comprising the ring system enhance lipid solubility Isopropyl chain
Secondary p-Fluoro-
F Carboxylic acid Hydrophilic due to its ability to ionize
phenyl(form an ion–dipole interaction with water) and to
ring
Hydroxyl participate in hydrogen bonding (acceptor and donor) in its unionized formIndole ring
Pravastatin Decalin ring
Fluvastatin
205
2.22PravastatinandFluvastatin
Shown below are the structures of pravastatin. A total of six functional groups have been boxed.
2. The log P values of pravastatin and fluvastatin are 1.44 and 3.62, respectively. Conduct a structural
analysis of these drug molecules F
and provide a structural explanation for the difference in these log P
C
values.
Answer
The log P valueBis a logarithmic expression of the ratio of a drug molecule’s solubility in a lipid
environment when compared to an aqueous environment D and assumes that all ionizable functional
groups are present in their unionized form. The log P value of any given drug molecule is the result
A the additive contributions and interrelationships of all of its functional groups. In evaluating the
of
structures of pravastatin and fluvastatin, both drug molecules contain a 3,5-dihydroxyheptanoic
acid group and differ in the ring systems attached to this group. The carboxylic acid and the two
secondary hydroxyl groups contribute to the water solubility of these drug molecules; however, it
E
would be expected that these contributions would be similar for both drug molecules. In evaluating
the different ring systems and their substituents, it can be seen that the structure of pravastatin
Pravastatin
contains an additional secondary hydroxyl group, as well as two ester oxygen atoms. These functional
Fluvastatin
groups are capable of forming additional hydrogen bonds and thus contribute to the overall water
solubility of pravastatin. The decalin ring and the isobutyl side chain contribute to the overall lipid
1. solubility
Using the of pravastatin.
table In contrast,
below, drophilic the remaining
or hydrophobic functional
in character. forgroups of fluvastatin—aromatic rings,
your response.
an aliphatic chain, and a halogen—contribute to its overall lipid solubility. It should be noted that
2. the
The lone
log Ppair
values of s and provide
of electrons presenta within
structural
theexplanation
indole ringfor
arethe difference
required forinthe
these log P values.
aromaticity of the ring
and therefore are not available to form hydrogen bonds or accept protons. Because the structure
Answer
of pravastatin contains more hydrophilic functional groups than the structure of fluvastatin, it has a
The log P value is a functional groups than the structure of fluvastatin, it has a lower log P value.
lower log P value.
3',5'-Dihydroxy-
heptanoic acid
Ester
Isobutyl chain
Isopropyl chain
Secondary p-Fluoro-
Hydroxyl phenyl ring
Indole ring
Pravastatin Decalin ring
Fluvastatin
3. The normal pKa range for carboxylic acids is 2.5 to 5. The pKa values for the carboxylic acids present
within the structures of pravastatin and fluvastatin are 4.21 and 4.56. Conduct a structural analysis
and provide a reason why these pKa values are at the high end of the normal range.
Answer
The presence or absence of specific functional groups can affect the acidity or basicity of ionizable
functional groups. In the case of pravastatin and fluvastatin, as well as other drug molecules within
this chemical/pharmacological class, the 3-hydroxyl group affects the acidity of the carboxylic acid. In
general, non-aromatic hydroxyl groups are electron withdrawing due to the high electronegativity of
the oxygen atom; however, in the case of pravastatin and fluvastatin, the position of the 3-hydroxyl
group orients it to form intramolecular hydrogen bonds with the carboxylic acid. These hydrogen
bonds decrease the ability of the proton of the carboxylic acid to dissociate, therefore decreasing its
acidity and increasing its pKa value.
Chapter2.22
2.22 Pravastatin and Fluvastatin 207

3. The normal pKa range for at the high end of the normal range.
Answer
Intramolecular
The presence or absence of its pKa value. Hydrogen Bond
Intramolecular
Hydrogen Bond H
Intramolecular O O
Hydrogen Bone H
O O
Intramolecular H O
Hydrogen Bone COOH
O
H OH
OH H
O
H
H3C O F
H Pravastatin N
H3C C H3 Fluvastatin

HO
4. Pravastatin and fluvastatin exert their hyperlipidemic effects by inhibiting the enzyme HMG CoA
reductase. As shownPravastatin
below, HMG CoA reductase converts 3-hydroxy-3-methylglutaryl CoA (HMG
Fluvastatin
CoA) to mevalonic acid. This conversion is required for the synthesis of cholesterol and acts as a
primary control site for production of this endogenous steroid. Using the structures of HMG CoA,
4. mevalonic acid,
Pravastatin andpravastatin, and fluvastatin,
fluvastatin fluvastatin, provide
provide an explanation
an d fluvastain inhibitas to how
HMG CoApravastatin
reductase. and fluvastatin
inhibit HMG CoA reductase.
HMG CoA
Reductase
Answer
In the reaction catalyzed by HMG CoA reductase, the thioester of HMG CoA is reduced to a primary
hydroxyl group. The 3,5-dihydoxyheptanoic acid found within the structures of pravastatin and
fluvastatin very nicely mimic the structure of mevalonic acid, the product of this reaction. Unlike the
natural substrate, pravastatin and fluvastatin cannot be reduced. Because they bear structural simi-
larity to both the substrate and the product, they can interact with the enzyme in a similar manner as
the substrate; however, because they lack the functional group that is normally reduced, they are not
transformed by the enzyme and act as enzyme inhibitors. The respective ring systems of pravastatin
and fluvastatin most likely occupy binding sites that are adjacent to the active site of the enzyme.
208 Answer
Answer
In the reaction most likely occupy binding sites that are adjacent to the active site of the enzyme.
In the reaction most likely occupy binding sites that are adjacent to the active site of the enzyme.
HMG CoA
HMG CoA
Reductase
Reductase Primary
Thioester Primary
Hydroxyl
Thioester Hydroxyl
HO 3
HO COOH
HO 3 3
COOH
HO 3
COOH 5 OH
COOH 5 OH
5 OH H
O 5 OH H
O H
H F
H3 C O
H3 C H
O F
H3 C C H3 N
H N
H3C C H3
HO
HO
Pravastatin
Pravastatin Fluvastatin
Fluvastatin
5. Shown below are the structures of fluvastatin and a conformationally restricted analog. The addition
of an additional carbon atom and the conformational restriction essentially abolish the therapeutic
5. Shown below are the structures why this structural change results in a loss in activity.
activity of fluvastatin.
5. Shown below areUsing these structures,
the structures postulatechange
why this structural a reason why this
results in a structural change results in
loss in activity.
a loss in activity.
Restricted Analog
ofRestricted Analog
Fluvastatin
of Fluvastatin
Answer
The addition of a functional group will affect the overall electronic distribution, water/lipid solu-
bility balance, and steric dimensions of the parent drug molecule. The electronic effects would be
expected to be minimal due to the low electronegativity values of carbon and hydrogen. The addi-
tional carbon atom will increase lipid solubility and this could affect the ability of the analog to
dissolve; however, the use of a sodium salt (similar to what is done with fluvastatin) should still allow
for adequate dissolution. This then leaves the steric effect as the most probable cause for the loss
2.22 Pravastatin and Fluvastatin 209
of activity with this analog. There are two aspects to consider. First, the addition of an extra carbon
atom may not be permitted due to the steric dimensions of the target enzyme, HMG CoA reductase.
The simple addition of a methyl group (or carbon atom) can significantly alter the interaction of a
drug molecule with its biological target. Although this may be the cause for the loss of activity, a
much bigger alteration in the steric dimension of fluvastatin has been introduced with this confor-
mational restriction. In evaluating the structure of fluvastatin, it is found that there is free rotation
about the bond that connects the indole ring to the para-fluoro aromatic ring. This allows flexibility
and the opportunity for these two rings to be oriented in a manner that allows optimal interactions
with HMG CoA reductase. In contrast, the conformational restriction introduced in the fluvastatin
analog creates a large, planar, tetracycline ring system with no flexibility. The ability of this analog to
interact with HMG CoA reductase would therefore be dependent on the availability of a complemen-
tary large, flat, hydrophobic area within the active site of the enzyme. Receptor binding studies have
shown that the para-fluoro aromatic ring of fluvastatin cannot be coplanar with the indole ring and
that conformational restriction, such as that shown in this question, abolishes therapeutic activity.
6. Pravastatin
6. Pravastatin is primarily
is primarily metabolite
metabolized to itsis3α
inactive.
epimer. This metabolite is completely inactive as an
HMG CoA reductase inhibitor. Identify the metabolic transformations required to produce this
metabolite and provide an explanation as to why this metabolite is inactive.
3D epimer
Answer
The epimer results from the oxidation of the 3β hydroxyl group by alcohol dehydrogenase followed
by reduction to the 3α epimer. The loss of activity results from the fact that the compound no longer
mimics HMG CoA or mevalonic acid. The epimeric hydroxyl group is oriented in the opposite direc-
tion and either fails to form a crucial hydrogen bond or sterically inhibits interaction with the active
site of HMG CoA reductase.
Answers
2.23 Quinapril
2.23 Quinapril
Shown belowbelow
Shown is the is
structure of quinapril.
the structure It is an
of quinapril. It angiotensin
is an groupsconverting enzyme (ACE) inhibitor that is used in the
are identified.
treatment of hypertension and heart failure. Five functional groups are identified.
B
H3C
O O D
A O
H
N
N
C
C H3
O
OH
E
1. Using the table below, identify the five boxed functional groups. For each of the functional groups you
1. Using
identified, the table
indicate below,
if it is identifyor
hydrophilic thehydrophobic
five explanation for your response.
in character. Also provide a brief explanation for
your response.
2. Using the h functional ionized or unionized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
Answer

A Phenyl ring; aromatic ring; aromatic Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional
hydrocarbon groups enhance lipid solubility.
B Ethyl ester Contains both hydrophilic and hydrophobic properties. The two oxygen atoms can act as
hydrogen bond acceptors and can contribute to water solubility. The ethyl group can neither
ionize nor form hydrogen bonds and thus contributes to lipid solubility.
C Secondary amine Hydrophilic due to its ability to ionize (form an ion–dipole interaction with water) and to
participate in hydrogen bonding (acceptor and donor) in its unionized form.
D Amide Secondary amine Carboxylic
Hydrophilic due to its ability to form hydrogen acid bond acceptor. (Note:
bonds as a hydrogen
Does not participate as a hydrogen bond donor due to the lack of hydrogen atom.)
E Carboxylic acid Hydrophilic due to its ability to ionize (form an ion–dipole interaction with water) and to
participate in hydrogen bonding (acceptor and donor) in its unionized form.

2. Using the unmodified structure of quinapril and the following table, identify all of the acidic and basic
functional groups present in the structure, provide the normal pKa range for each functional group, and
identify if each functional group would be primarily ionized or unionized at pH environments=1.5, 4.8,
6.3, 7.4, and 8.1.
211
E
H3C
212 1.Medicinal
Using the table below,
Chemistry identify theOfive explanation
Self Assessment O for your response.
D
2. Using the h functional ionized
A or unionized atOpH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
H
N
N
C
C H3
O
OH
E
1. Using the table below, identify the five explanation for your response.
2. Using the h functional ionized or unionized at pH environments of 1.5, 4.8, 6.3, 7.4, and 8.1.
Secondary amine Carboxylic acid

Secondary amine Basic 9–11 Ionized Ionized Ionized Ionized Ionized
Carboxylic acid Acidic 2.5–5 Unionized Ionized* Ionized Ionized Ionized
*There is a possibility that this functional group could be > 50% unionized at a pH=4.8; however,
because the pKa values of carboxylic acids present in the structures of other drug molecules within
Secondary amine class tend to range from 2.3 to 3.5, Carboxylic
this chemical/pharmacological this functional
acid group will most
likely be primarily ionized at this pH value.
3. Quinapril is a prodrug. It is administered as an oral tablet and converted in vivo to its active metabo-
3. quinaprilat.
lite, Quinapril is Identify
a is administered orally instead
the metabolic of quinaprilat.
pathway that converts quinapril to quinaprilat, and offer a
reason why quinapril is administered orally instead of quinaprilat.
Answer
Ester hydrolysis converts quinapril to quinaprilat. Esterases are ubiquitous within the human body
and can readily convert ester prodrugs to their active forms. In evaluating the structures of quinapril
and quinaprilat, the only difference in these two molecules is the presence of a second carboxylic
acid in quinaprilat instead of the ethyl ester present in quinapril. Both of these molecules possess
a sufficient number of water soluble functional groups to allow for their dissolution within the
aqueous content of the GI tract. Quinaprilat has three ionizable functional groups (two carboxylic
acids and a secondary amine) along with an amide that is capable of forming hydrogen bonds. This
greatly enhances the water solubility of quinaprilat to the extent that it has difficulty traversing the
GI membrane despite the presence of hydrophobic rings and alkyl chains. To optimize the water/lipid
balance, an ester prodrug is used. The ethyl ester is more hydrophobic than the carboxylic acid and in
combination with the other hydrophobic groups allows for better passage across the GI membrane.

2.23 Quinapril 213
Chapters1.23and2.23
4. Quinapril inhibits ACE. This enzyme is a relatively nonspecific dipeptidyl carboxypeptidase. It is a zinc
protease that converts angiotensin I, a decapeptide, to angiotensin II, an octapeptide. The peptide
4. cleavage
Quinapril isinhibits
providedbelow. catalyzed
ACE.by the zinc
binding atom andare
interactions is shown below.
occurring Quinapril,
at a pH of 7.4. along with other ACE inhibi-
tors, is a tripeptide mimic that can interact with the enzyme resulting in enzyme inhibition rather
than hydrolysis. Using this information and the structures provided below, identify how quinapril can
interact with ACE. Assume that all drug binding interactions are occurring at a pH=7.4.
Leu
Leu
Phe His
His
Phe Quinaprilat
Angiotensin I
Quinaprilat
R = Asp-Arg-Val-Tyr-Ile-His
Angiotensin I
Answer
Answer
B
C
Because ACE is a nonspecific dipeptidyl carboxypeptidase, it is able to hydrolyze a dipeptide sequence

from the carboxylic acid end of a peptide. For this enzyme to be able to cleave a dipeptide sequence
(i.e., two amino acids), substrates must have a minimum length of three amino acids. Quinaprilat and
other ACE inhibitors act as tripeptide mimics. These drug molecules retain key peptide features (i.e.,
peptide bonds, side chains similar to those found on amino acids), but are not able to be hydrolyzed.
Thus, they are able to interact in a similar manner as the substrate does. The table below lists five key
interactions of quinaprilat with ACE.
Drug Binding
Interaction Explanation
A Ionic interaction This carboxylic acid mimics the C-terminal carboxylic acid of an ACE substrate and
will participate in an ionic interaction with the side chain of either Asp or Glu.
B van der Waals and/or hydrophobic Because ACE is a nonspecific carboxypeptidase, quinapril does not need to exactly
binding with hydrophobic amino mimic Leu, the C-terminal amino acid of angiotensin I. Similar to the side chain of
acids (e.g., Phe, Tyr, Leu, Ile) Leu, this ring system is hydrophobic and can participate in similar types of interac-
tions as Leu.

C Hydrogen bond acceptor Because ACE is a dipeptidyl carboxypeptidase, it does not cleave the terminal
peptide bond. Instead, the terminal peptide bond can participate in hydrogen
bonds. The carbonyl of the amide bond can act as a hydrogen bond acceptor and
interact with Ser, Thr, Tyr, Trp, Gln, Asn, or Cys.
D Ionic bond (metal complexation) This carboxylic acid would be located very close to the zinc atom shown partici-
pating in the mechanism of angiotensin I metabolism. As such, at pH=7 it can
form an ionic bond with the zinc atom.
E van der Waals and/or hydrophobic This aromatic ring mimics the Phe side chain of angiotensin I and can participate
binding with hydrophobic amino in similar interactions.
acids (e.g., Phe, Tyr, Trp)
5. Shown below are in these pathways.

5. Shown below are four possible metabolic pathways for quinapril. Identify the metabolic transforma-
Answer
tions involved in these pathways.
A B
Quinapril
C D
Answer
• Pathway A: Aromatic oxidation followed by sulfate conjugation of the resulting phenol
• Pathway B: Ester hydrolysis
• .Pathway C: Amino acid conjugation (with glycine)
• Pathway D: Benzylic oxidation followed by oxidation of the resulting secondary alcohol
2.23 Quinapril 215
6. Although it is possible for quinapril to undergo all of the above metabolic transformations, pathway
B is the major pathway. Other metabolites have been identified, but only at very low levels. Provide
an explanation for this finding.
Answer
Remember that the major purpose of drug metabolism is to enhance the removal of the drug from
the body, and the number of metabolic transformations required to achieve this goal varies from
drug molecule to drug molecule. In the case of quinapril, ester hydrolysis can occur quickly and at
many locations within the body. The resulting metabolite, quinaprilat, contains three ionizable func-
tional groups and is easily eliminated from the body without the need for further metabolism.
Answers
2.24 Rivastigmine
2.24Rivastigmine
Shown below is the structure of rivastigmine. Four of its functional groups have been identified.
Shown below is the structure of rivastigmine. Four of its functional groups have been identified.
C H3 C CH3 D
A H3C N O C H3
N
O C H3
B
Rivastigmine
1. Using1.theUsing
tablethe tableidentify the four boxed functional groups. For each of the functional groups you
below,
identified, indicate if it induction.
2. Based on their is hydrophilic or hydrophobic in character. Also provide a brief explanation for
your response.
3. Rivastigmine is an acetylcholinesterase with acetylcholine.
Answer

Labile ester bond
A Alkyl chain; alkyl group; aliphatic chain Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional
groups enhance lipid solubility
B Carbamate Hydrophilic due to its ability to act as a hydrogen bond acceptor
C Phenyl ring; aromatic ring; aromatic Hydrophobic due to its inability to ionize or form hydrogen bonds; hydrocarbon functional
hydrocarbon groups enhance lipid solubility
D Tertiary amine Hydrophilic due to its ability to ionize (form an ion–dipole interaction with water) and to
participate in hydrogen bonding (acceptor) in its unionized form
Rivastigmine
groups A and B are electron withdrawing or electron donating. Additionally, identify if this effect is due
to resonance or induction.
Answer Acetylcholine bound to active site
• Functional group A is an alkyl (ethyl) group and has a lower electronegativity than the nitrogen atom
of the carbamate; therefore, it acts as an electron donating group through induction. The same is true
for the twoA.methyl groups
Conduct attached analysis
a structural to the tertiary
of howamine.
it could interact with acetylcholinestase.
• Functional group B is a carbamate
Answer:al group
groups to orient that is directly
themselves attached
in a similar to an
manner aromatic
within ring. Based
the enzyme onsite.
binding its
position, it can donate electrons into the aromatic ring through resonance.
B B
A
A
217
Key structural similarities
A 3 3
N
O C H3
2.24Rivastigmine
B
Shown below is the structure of rivastigmine. FourRivastigmine
of its functional groups have been identified.
3. Rivastigmine is an acetylcholinesterase inhibitor. Inhibition of this enzyme prolongs the half-life of

1.acetylcholine,
Using the table C H3
allowing for higher concentrations CH3 D
C of acetylcholine at muscarinic and nicotinic recep-
tors. This action is useful in
A H3C
2. Based on their induction. the treatment
N O of Alzheimer’s disease,
C H3 myasthenia gravis, and glaucoma.
Shown below is the structure of acetylcholine interacting Nwith the active site of acetylcholinesterase.
3.Glutamic
Rivastigmine is an acetylcholinesterase
acid, histidine, with acetylcholine.
and serine are involved in the mechanism of ester hydrolysis and can form
O C H3
specific interactions with acetylcholine.
B
Labile ester bond Rivastigmine
1. Using the table

2. Based on their induction.
3. Rivastigmine is an acetylcholinesterase with acetylcholine.
Labile ester bond
Rivastigmine
Acetylcholine bound to active site

a. Conduct
A. aConduct
structural analysis of
a structural rivastigmine
analysis of how and indicate
it could how
interact it acetylcholinestase.
with could interact with acetylcholin-
esterase.
Answer:al groups to orient themselves in a similar manner within the enzyme binding site.
Rivastigmine
Answer
The structure of rivastigmine contains a tertiary amine that will be primarily ionized at a physi-
ological pH=7.4. This ionized B amine mimics the quaternary nitrogen present B within the structure
of Acetylcholine
acetylcholinebound
and can
to form site
active an ionic interaction withA the glutamic acid or with the side chain
A
of another acidic amino acid (comparison A). The carbamate present within the structure of
rivastigmine is isosteric to the acetate ester of acetylcholine and thus can form similar hydrogen
bonds (comparison B). The distance between the tertiary amine and the carbamate of rivastig-
A. Conduct a structural analysis of how it could interact with acetylcholinestase.
mine is two carbon atoms longer than the quaternary nitrogen and the acetate of acetylcholine;
Answer:al
however, groups to orient
conformational themselves
rotation in astructure
within the similar manner within the allows
of rivastigmine enzymethese
binding site.
functional
Key structural similarities
groups to orient themselves in a similar manner within the enzyme binding site.
B B
A
A
Key structural
Similar distances similarities
after conformational rotation
(Note: The length of the lines are identical)
Similar distances after conformational rotation

(Note: The length of the lines are identical)
2.24 Rivastigmine 219
b. The serine residue of acetylcholinesterase attacks the ester bond of acetylcholine causing hydro-
lysis and acetylation of the serine. A similar reaction occurs between the carbamate group of
rivastigmine and the serine residue; however, while acetylcholine is a substrate of acetylcholin-
B.
esterase,The serine residue
rivastigmine is aninhibits acetylcholinesterase.
inhibitor. Compare the functional groups involved and provide an
explanation as to how rivastigmine inhibits acetylcholinesterase.
B. The serine residue inhibits acetylcholinesterase.

rivastigmine
4. Answer
Neostigmine is a structural analog in routes of administration.
In both cases, acetylcholinesterase catalyzes the hydrolysis of a functional group. As part of this
mechanism, serine makes a bond that is similar to that which was hydrolyzed. In the case of
acetylcholine, serine is esterified (i.e., an ester is added to the serine side chain). Esters can be
very rapidly hydrolyzed; therefore, acetylcholinesterase is very quickly regenerated and acetyl-
choline acts as a substrate. In the case of rivastigmine, serine is carbamylated (i.e., a carbamate
group is added to the serine side chain). Unlike esters, carbamates are hydrolyzed much slower;
thus, the intermediate shown above persists for much longer than the millisecond that it takes to
hydrolyze an ester. As a result, the carbamate + portion of rivastigmine remains attached to acetyl-
cholinesterase for a longer time resulting in inactivation of the enzyme.
Neostigmine Bromide
4. Neostigmine is a structural analog of rivastigmine. Similar to rivastigmine, neostigmine is able to

interact with acetylcholinesterase and cause inhibition due to the presence of a carbamate functional
5. group.
Rivastigmine has aindifference
Intermediate
The primary results
the hydrolysis
differences of in a longer
between durationand
rivastigmine of action.
neostigmine are their routes of admin-
acetylcholine
istration and their Analogousorally
therapeutic indications. Rivastigmine is administered intermediate formed withof
in the treatment
rivastigmine
Alzheimer’s disease, whereas neostigmine is administered intramuscularly (IM) or subcutaneously
Methyl of myasthenia gravis. Conduct structural analyses of these drug molecules and
(SC) in the treatment Methyl
4. provide
Neostigmine is a structural
an explanation foranalog
these in routes of administration.
differences in routes of administration and therapeutic indications.
Methyl
Ethyl
+
+
Neostigmine Bromide
5. Rivastigmine has a difference results in a longer duration of action.

220 Intermediate
Medicinal in the
Chemistry hydrolysis
Self of
Assessment
rivastigmine
Answer
4. Neostigmine is a structural analog in routes of administration.
Unlike rivastigmine, the structure of neostigmine contains a permanently charged ammonium salt.
Similar to the tartrate salt of rivastigmine, this will enhance water solubility; however, it will hinder
the ability of the neostigmine to be absorbed within the gastrointestinal tract and to cross the
blood–brain barrier. Therefore, neostigmine cannot be administered orally nor can it be used to treat
Alzheimer’s disease because it is unable to reach its site of action in the central nervous system (CNS).
Neostigmine is well suited for IM and SC administration and can be used to treat myasthenia gravis,
a chronic autoimmune neuromuscular disorder that is characterized by fluctuating weakness of the
+
voluntary muscle groups in the periphery. The beneficial effects of acetylcholinesterase inhibition
observed in the treatment of myasthenia gravis do not require that the drug molecule enter the CNS.
Neostigmine Bromide
5. Rivastigmine has a longer duration of action than neostigmine. A comparison of the structures of
rivastigmine and neostigmine reveals that the carbamate group present in rivastigmine is slightly
5. larger
Rivastigmine haspresent
than that a difference results in a Using
in neostigmine. longer the
duration of action.
mechanism of action given in question 3, provide
a reason why this structural difference results in a longer duration of action.
Methyl
Methyl
Methyl
Ethyl
+
Answer
The mechanism of action of these two drug molecules involves the carbamylation of the serine
residue found within the active site of acetylcholinesterase and the subsequent slow hydrolysis of
the carbamate. As the size of the carbamate increases, hydrolysis and regeneration of acetylcholines-
terase decreases. So in this case, the additional carbon atom present within the structure of rivastig-
mine provides steric hindrance to the hydrolysis of the carbamate resulting in a longer duration of
action.
6. Evaluation of the structure of rivastigmine reveals that the aliphatic chain containing the tertiary
amine is located meta to the carbamate group. Similar orientations can be seen with neostigmine.
Using the information from the previous questions, provide an explanation as to why a para
orientation of these
6. Evaluation of thefunctional groups would lead to a significant decrease in the ability to inhibit
to inhibit acetylcholinesterase.
acetylcholinesterase.
meta orientation para orientation

C H3 C H3 C H3
H3 C N O C H3 C H3
N O N
O C H3 C H3
H3C N O
C H3 para Analog of
Rivastigmine
Rivastigmine
Answer
Answer:
For rivastigmine to interact with acetylcholinesterase, it must contain structural features that mimic
For rivastigmine
acetylcholine, to interact
the natural with acetylcholinesterase,
substrate it must contain
for this enzyme. As previously structural
explained features 3,
in question that mimic
the
3 3
H3 C N O C H3 C H3
N O N
O C H3 CH
2.24
3 Rivastigmine 221
H3C N O
C H3 para Analog of
Rivastigmine
tertiary amine and carbamate of rivastigmine can mimic the quaternary Rivastigmine
nitrogen atom and ester of
acetylcholine respectively. The aromatic ring provides structural rigidity; however, conformational
flexibility of its substituents allows these functional groups to be properly oriented when they are
Answer:
located meta to one another. As shown below, para orientation of these substituents does not allow
forrivastigmine
For proper orientation.
to interactAlthough the requisite functional
with acetylcholinesterase, groupsstructural
it must contain are present, they that
features are located
mimic too far
apart from one another and, therefore, cannot interact effectively with acetylcholinesterase.
The meta orientation allows for similar distances
The para orientation places the functional groups

too far apart from one another
Answers
2.25 Sitagliptin
Sitagliptin is an inhibitor of dipeptidyl peptidase IV (DPP-IV), a serine protease that catalyzes the deactivation/degra-
2.25 Sitagliptin
dation of GLP-1. GLP-1 is a 36-amino acid peptide that is responsible for promoting insulin secretion in response to
an increase in blood glucose levels. Currently there are four DPP-IV inhibitors on the market, all of which contain an
essential basic amino functional group that represents the penultimate amino-terminal alanine residue found within
GLP-1.Sitagliptin is an inhibitor of dipeptidyl represents the amino-terminal alanine residue found within GLP-1.
A
F
B C
F
N H2 O
D
N
N
N
F N
CF3
Sitagliptin
Sitagliptin
1. Conduct a structural evaluation of sitagliptin, focusing on the boxed functional groups, and use the infor-
mation1.in the grid to
Conduct inform
a grid the answers
to inform to the
the answers to questions thatthat
the questions follow.
follow.
Answer
2. Sitagliptin is group and modify the structure to show the phosphate salt form.
Function
Character Function Amino Acids That
Acidic, Basic, Interaction(s) Can Interact with the
Character F
or Neutral Function Functional Group via
Possible with
Name of Hydrophilic FProvide ↑ Solubility Biological Target Ion–Dipole Interactions
Functional and/or pKa When N H2 O
and/or at Physiological at pH=7.4
Group Hydrophobic Relevant ↑ Absorption pH=7.4N None Is Acceptable
A
N
Halogenated Hydrophilic (F) Neutral Solubility (F) N
van der Waals Asp, Glu, Lys, Arg
aromatic Hydrophobic (R) F Absorption (R) N
Hydrophobic
hydrocarbon
H-bondingCF
(A)
3
Sitagliptin Dipole–dipole
Answer: dipole)
π-π stacking
The pKa the primary amine is the most basic functional group within the structure of sitagliptin.
B Primary amine Hydrophilic (NH2) Basic Solubility (NH2) Ion–dipole (as the Ser, Thr, Tyr, Cys, Asn, Gln,
Hydrophobic (R) pKa 9–11 Absorption (R) ion) Trp, His
Ionic
223
Sitagliptin is an inhibitor of dipeptidyl represents the amino-terminal alanine residue found within GLP-1.
224 Medicinal
Sitagliptin is anChemistry
inhibitor ofSelf
A
Assessment
dipeptidyl represents the amino-terminal alanine residue found within GLP-1.
F
B C
F A
Continued from previous page. N H2 O
F D
B C N
C Amide Hydrophilic F Neutral Solubility (CON) H-bonding (A) Asp, Glu, Lys, Arg
N
2 O
N H Absorption
D N
(CON) (R) Dipole–dipole
Hydrophobic (R) F N
Ion–dipole
N (as the
N dipole)
N CF3
D Aromatic Hydrophilic (N) F
Basic Sitagliptin
Solubility (N) N H-bonding (A) Asp, Glu, Lys, Arg
Heterocycle Hydrophobic (R) pKa ~1-5 Absorption (R) Dipole–dipole
(1, 3, 4 CF 3
triazole) Sitagliptin Ion–dipole (as the
dipole)
1. Conduct a grid to inform the answers to the questions that follow.
1. Conduct
2. Sitagliptin a grid to inform
is formulated the answers
as a phosphate to the
salt. questions
Identify that follow.
the most basic functional group and modify the
structure to show the phosphate salt form.
F
F
N H2 O
F
F N
N
N H2 O N
F N
N
N
N CF3
F Sitagliptin
Sitagliptin N
Answer
Answer: CF3
Sitagliptin
The pKa of the aromatic heterocycle (1,3,4-triazole) is much lower than the pKa of the primary amine.
There is The
one pK a the primary
additional amine
nitrogen is thethat
atom most
youbasic
mightfunctional group within
be considering. Be the structure ofnitrogen
careful—that sitagliptin.
atom
Answer:
is directly attached to a carbonyl (to form an amide) and is neutral in character! With the analysis
complete,
The itpKisa clear that the primary amine
the primary amine is the most isbasic
the most basicgroup
functional functional
within group withinofthe
the structure structure of
sitagliptin.
sitagliptin.
Sitagliptinphosphate
3. Sitagliptin is marketed as the R-enantiomer. Evaluate the structure of sitagliptin and provide a struc-
tural rationale for the R-enantiomer designation.
Answer
Using the Cahn-Ingold-Prelog (CIP) (see Chapter 7 in Basic Concepts in Medicinal Chemistry), the four
groups attached to the chiral carbon atom need to be prioritized based on atomic number and the
described sequence rules. Using these rules, the primary amine nitrogen atom is prioritized as #1 as it
has the highest atomic number, the methylene unit attached to the amide carbonyl is prioritized as
#2, the methylene unit attached to the halogenated aromatic hydrocarbon is prioritized as #3, and
the hydrogen atom pointing away from the reader is the #4 priority. NOTE: it is important to recog-
nize that although the methylene units are identical, the rules state that atoms attached to each of
these methylene units are the next to be evaluated. Evaluation of the methylene to the right of the
2.25 Sitagliptin 225
3. Sitagliptin is designation.
primary amine reveals that the carbon atom is attached to the equivalent of two oxygen atoms and a
nitrogen atom. Evaluation of the methylene to the left of the primary amine reveals that the carbon
Answer:
atom is attached to the equivalent of three carbon atoms. The atomic number of both oxygen and
Using
nitrogen the Cahn-Ingold-Prelog
is higher (are clockwise
than carbon; therefore, in orientation
the #2 and and the R-enantiomer
#3 prioritization is reflective ofisthat
drawn.
analysis.
Reviewing the positions of these priorities, it is noted that they are clockwise in orientation and the
R-enantiomer is drawn.
3 2
4
Sitagliptin
Sitagliptin
4. At 38%, the fraction of sitagliptin reversibly bound to plasma proteins is relatively low. By way of
4. At 38%,
reminder, only the
thebound (e.g.,fraction
unbound warfarin).
of drug is able to exert its biological activity and undergo
metabolism. Describe the relative risk of a plasma protein binding interaction between sitagliptin
and5.another
Approximately 79%
drug that of urine.
is highly Provide
protein a abolic
bound transformation
(e.g., warfarin). (i.e., excreted unchanged).
Answer
Based on the information from the structure evaluation grid, sitagliptin is a basic drug (see discussion
of 6.
the Assess
plasma each of the
binding liptin and
proteins determine
in Chapter which
3 of phase
Basic I metabolic
Concepts transformation
in Medicinal hasfor
Chemistry occurred.
information
about albumin and α1-acid glycoprotein). Generally albumin tends to bind to acidic drugs, whereas
the plasma protein α1-acid glycoprotein has an affinity for basic drugs and some neutral drugs.
Warfarin is an acidic drug and is greater than 90% plasma protein bound. In this scenario, warfarin
would be bound to albumin and sitagliptin would be bound to α1-acid glycoprotein. Because the
two drugs are not competing for the same plasma binding protein, there is very, very little risk of a
plasma protein binding interaction.
5. Approximately 79% of sitagliptin is excreted unchanged in the urine. Provide a structural rationale
that supports this observation.
Answer
Based on the information in the structure evaluation grid, sitagliptin contains a number of func-
tional groups that contribute to the overall water solubility of the drug. The fluorinated aromatic
hydrocarbon, amide, and aromatic heterocycle (1,3,4 triazole) will be able to participate in important
hydrogen bonding interactions with water. The primary amine, likely to be predominantly ionized in
the plasma and urine, significantly enhances this water solubility by participating in the strong ion–
dipole interactions with water. The drug is sufficiently hydrophilic in character for it to be excreted
without the need for metabolic transformation (i.e., excreted unchanged).
6. Assess each of the possible metabolic products generated from sitagliptin and determine which
phase I metabolic transformation has occurred.
C
D
Answer
A Benzylic oxidation
B Oxidative deamination
C Amide hydrolysis
D Aromatic hydroxylation
Answers
2.26 Sorafenib
Because protein tyrosine kinases regulate cellular proliferation, differentiation, and survival, it is no surprise that
several neoplastic disorders can be tied to altered activity of protein tyrosine kinases. Clinically relevant antineo-
plastic tyrosine kinase inhibitors interact with the active site of the enzyme via several types of binding interactions.
The adenosine triphosphate (ATP) binding domain of the tyrosine kinases contains a hydrophobic domain that
includes a significant number of isoleucine, leucine, alanine and valine residues. There are at least five binding pockets
that flank this region in which van der Waals, hydrophobic, hydrogen bonding, and electrostatic interactions occur.
Sorafenib is a tyrosine kinase inhibitor used in the treatment of advanced renal cell carcinoma, a highly vascularized
tumor.2.26
The Sorafenib
drug specifically targets vascular endothelin growth factor 2 (VEGF2) that is instrumental in the genera-
tion ofBecause
new blood vessels.
protein tyrosine kinases owth is instrumental in the generation of new blood vessels.
C F
E
B D
Sorafenib
Sorafenib
1. Conduct
1. aConduct
structural evaluation
a to of sorafenib,
the questions that follow.focusing on the boxed functional groups, and use the infor-
mation in the grid to inform your answers to the questions that follow.
2. Sorafenib interacts with in the local environment of the enzyme.
3. Nilotinib, another and Leu298/Val299/Phe359 in each of the respective five binding pockets.
B C D E
Nilotinib
227
A. Consider the side chains of the. Assume pH=7.4.

Answer
Character
Acidic, Basic, Function

Interaction(s)
Hydrophilic Provide ↑ Solubility Possible with Biological
Name of and/or pKa When and/or Target at Physiological
Functional Group Hydrophobic Relevant ↑ Absorption pH=7.4
A Halogenated aromatic Hydrophobic Neutral Absorption Cl:
hydrocarbon Dipole–dipole
Ar:
van der Waals
Hydrophobic
π-π Stacking
B Halogenated aliphatic Hydrophilic (F) Neutral Solubility H-bonding (A)
alkane Dipole–dipole
C Urea Hydrophilic (HNCONH) Neutral Solubility (HNCONH) H-bonding (A + D)
D Ether Hydrophilic (O) Neutral Solubility (O) H-bonding (A)
E Pyridine Hydrophilic (N) Basic Solubility (N) Pyridine N atom:
(Azine) Hydrophobic (R) (pKa 1–5) Absorption (R) H-bonding (A)
Dipole–dipole
R:
van der Waals
Hydrophobic
π-π Stacking
F Amide Hydrophilic (CONH) Neutral Solubility (CONH) H-bonding (A+ D)
2. Sorafenib interacts with Cys919, Phe1047, and Asp1046 via hydrogen bonding and hydrophobic interactions.
Identify which functional groups could interact with the side chains of these amino acids. Assume
that Asp1046 is unionized in the local environment of the enzyme.
2.26 Sorafenib 229
2.26 Sorafenib
Because
Answer protein tyrosine kinases owth is instrumental in the generation of new blood vessels.
Interacts with Cysteine919 Interacts with Aspartic Acid1046 Interacts with
via a Hydrogen Bonding
C via a Hydrogen Bonding
F Phenylalanine1047 via a
Interaction Interaction Hydrophobic Interaction
Functional E
A No A No Yes
B Yes Yes No
C Yes Yes No
D Yes B Yes D No
E Yes Yes Yes
F Yes Sorafenib
Yes No
1. Conduct a to the questions that follow.

3. Nilotinib, another tyrosine kinase inhibitor (via Bcr-Abl) indicated for the treatment of Philadel-
phia2.Chromosome
Sorafenib interacts with in the
(Ph+) positive localmyelogenous
chronic environment ofleukemia,
the enzyme.
also interacts with each of the five
binding pockets found within this 298 biological
299 target. This drug interacts with Leu285/Val289, Asp391/Glu286,
359
3. , Met
Thr315 Nilotinib,
318
andanother and299
Leu298/Val Leu /Val
/Phe359 /Pheof
in each in each
the of the respective
respective fivepockets.
five binding binding pockets.
B C D E
Nilotinib
Nilotinib
a. Consider the side chains of the amino acids indicated and determine which type(s) of binding
interactions are possible in each of the five binding pockets. Assume pH=7.4.
Answer
A. Consider the side chains of the. Assume pH=7.4.
B. Determine which of the side chains are both at pH=7.4.
Hydrophobic Ionic H-bonding Hydrophobic Hydrophobic
C. It has beenIon–dipole
van der Waals atom(s) (as
within the structure
the ion) of methionine
Dipole–dipole participate in thisvaninteraction.
Dipole–dipole der Waals
Ion–dipole (as the van der Waals
dipole)
Methionine
B D
Sorafenib
b. 1. Conductwhich
Determine a to the
of questions
the boxedthat follow. groups (A–E) can interact with the side chains of the
functional
amino acids found in each of the five binding pockets. Indicate the type of interaction(s) possible
2. Sorafenib interacts with in the local environment of the enzyme.
in the appropriate box. None is an acceptable answer. Assume that the drug and the amino acid
side chains are both at pH=7.4.
3. Nilotinib, another and Leu298/Val299/Phe359 in each of the respective five binding pockets.
Leu285/Val289
AAsp /Glu286 Thr315 Met318 Leu298/Val299/Phe359
391
A Hydrophobic Ion–dipole (functional H-bonding (A) Hydrophobic Hydrophobic

group as the dipole) Dipole–dipole π-π Stacking
B C D E
B Hydrophobic None H-bonding (A) Hydrophobic Hydrophobic
van der Waals Dipole–dipole van der Waals
π-π Stacking
C None Ion–dipole (functional H-bonding (A+D) None None
group as the dipole) Dipole–dipole
D* None Ion–dipole (functional H-bonding (A+D) None None
group as the dipole) Dipole–dipole
E** Hydrophobic Ion–dipole (functional Nilotinib
H-bonding (A) None Hydrophobic
group as the dipole) Dipole–dipole π-π Stacking
* Aniline-like nitrogen atom will not be ionized at physiological pH.

A. (azine)
**Pyridine Consider the sideatom
nitrogen chains of not
will the. be
Assume pH=7.4.
ionized at physiological pH.
B. Determine
c. It has been documentedwhich
thatofthe
the pyridyl
side chains are both
nitrogen at (functional
atom pH=7.4. group E) of nilotinib partici-
pates in a hydrogen bonding interaction with methionine. Draw a diagram that clearly shows
C. It has
which atom(s) beenthe
within atom(s) withinofthe
structure structure ofparticipate
methionine methionineinparticipate in this interaction.
this interaction.
Answer: Methionine
Methionine
Answer
H-Bond
Acceptor
Nilotinib
Nilotinib
H-Bond
Donor
Methionine
Methionine
2.26 Sorafenib 231
4. Sorafenib enters cells via passive diffusion. Using the information in the structure evaluation grid as a
starting point, identify which functional groups contribute to the ability of this drug to enter cells via
passive diffusion.
Answer
The halogenated aromatic hydrocarbon, aromatic hydrocarbon, and the pyridine ring carbon atoms
all contribute significantly to the hydrophobic character of sorafenib. It is important to note that
the basic pyridine ring is unlikely to be ionized at physiological pH (pKa = 6 < pH = 7.4). Although
there appears to be significant hydrophilic character (halogenated aliphatic alkane, urea, ether, the
nitrogen atom of the pyridine, amide) present in this molecule, sorafenib is practically insoluble in
water. The lack of water solubility and clearly identifiable hydrophobic character allows for passive
diffusion of the drug across the cellular lipid bilayer membrane.
5. Nilotinib is considered significantly more hydrophobic than sorafenib (distribution coefficient log D is
2.4 and 0.8 respectively). Provide a structural rationale for this property difference.
Answer
Based on the information found in the structure evaluation grid for sorafenib, there are several
functional groups that contribute to the overall hydrophobic character of the molecule (e.g., halo-
genated aromatic hydrocarbon, aromatic hydrocarbon, carbon atoms of pyridine/azine ring). Similar
evaluation of nilotinib yields two aromatic rings, a pyrimidine ring (between functional groups D and
E), a pyridine ring (functional group E), and even some hydrophobic character in the histidine ring
(functional group A) that contribute to the overall hydrophobic character of the molecule. When you
compare the sheer number of functional groups that contribute to the overall hydrophobic character
for each drug, nilotinib wins!
6. Sorafenib is marketed as a tosylate salt, a lipid-soluble organic salt. Nilotinib is marketed as a hydro-
chloride monohydrate salt, an inorganic salt. In general, what is the value of each of these types of
salts?
Answer
The value of lipid-soluble organic salts is to decrease the water solubility and increase the lipid solu-
bility of the parent drug (in this case sorafenib) (see Chapter 5 of Basic Concepts in Medicinal Chem-
istry). Typically lipid-soluble salts are used in the formation of lipid-soluble suspensions. In addition,
they can improve the oral bioavailability of acid labile drug molecules and improve the palatability
of liquid solutions. p-Toluenesulfonic acid (tosylic acid) is considered a strong organic acid and forms
a strong counter-ion when dissociated from the drug molecule. Sorafenib is administered as a film-
coated tablet for adults and as a liquid suspension for children.
The value associated with the formation of inorganic salts is due to the improved aqueous solubility,
solvation, and dissolution that results. In general, inorganic salts enhance the absorption of drugs
that are administered orally because they improve both solvation and dissolution properties.
Answers

Shown below
Shown is the
below is structure of zanamivir.
the structure This drug
for the treatment of molecule
influenza is
A administered via oral inhalation for the treatment of
and B infections.
influenza A and B infections.
Zanamivir
Chapter2.27
1. Identify all of the
1. Identify acidic
all of the ofand
7.2.basic functional groups, provide the normal pKa range for each functional
group, and identify if each functional group would be primarily ionized or unionized at a pulmonary
PleasereplacethestructurefortheanswerofQ1withtheonebelow.
Answer:
pH=7.2.
Answer
Carboxylic acid (Acidic functional group)

Carboxylic
Normalacid
pH (Acidic
range =functional
2.5 to 5 group)
Normal pH range
Would = 2.5 toionized
be primarily 5 at a pH of 7.2
Would be primarily ionized at a pH = 7.2
Guanidine (Basic functional group)

Guanidine
Normal(Basic functional
pH range group)
= 12 to 13
Normal pH range
Would = 12 toionized
be primarily 13 at a pH of 7.2
Answer:
Please replace the structure for the answer to Q6, part a with the one below (page 4, middle structure)
Primary hydroxyl group Secondary hydroxyl group
(or primary alcohol) (or secondary alcohol)
Secondary hydroxyl group
(or secondary alcohol) Ether oxygen
233
Guanidine (Basic functional group)
Normal pH range = 12 to 13
Would be primarily ionized at a pH of 7.2
Answer:
Answer
Primary hydroxyl group Secondary hydroxyl group

(or primary alcohol) (or secondary alcohol)
Secondary hydroxyl group
(or secondary alcohol) Ether oxygen
Amide
The amide and hydroxyl groups can act as hydrogen bond donors and acceptors and thus can form
hydrogen bonds with water. The ether oxygen most likely contributes the least to water solubility;
however, it can on
3. Based function
your isas a hydrogenasbond
administered acceptor.
an oral inhaler instead of an oral tablet or capsule.
3. Based on your answers to questions 1 and 2, explain why zanamivir is administered as an oral inhaler
instead of an oral tablet or capsule.
Answer
The structure of zanamivir contains multiple hydrophilic functional groups that will allow it to easily
dissolve within the aqueous contents of the gastrointestinal (GI) tract. The carboxylic acid and the
guanidine functional groups will be extensively ionized at an intestinal pH=5 which further increases
the overall water solubility of the molecule. Although the structure of zanamivir contains a hydro-
carbon chain and ring, the overall balance between water and lipid solubility hinders its ability
to effectively cross the GI membrane. The oral absorption of zanamivir has been reported to be
between 1% and 5%. Due to this, zanamivir must be administered via oral inhalation.
4. Zanamivir exerts its antiviral action by inhibiting neuraminidase, a viral enzyme that is required for
the spread of the viral infection. A key component of neuraminidase’s action is the hydrolysis of
4. Zanamiviracid
N-acetylsialic exerts
fromitssurface
his, provide an explanation Shown
viral glycoproteins. how zanamivir
below isinhibits neuraminidase.
the structure of N-acetylsialic acid
bound to a glycoprotein. Using this structure and the structure of zanamivir, provide an explanation
of how zanamivir inhibits neuraminidase.
Glycosidic bond
Answer
Answer:
Zanamivir is a stable mimic of N-acetylsialic acid. As shown below, the structure of zanamivir retains
many Zanamivir is a stable
of the structural a cleavable
features glycosidic bond.
of N-acetylsialic acid, but lacks a cleavable glycosidic bond.
Structurally identical
to N-acetylsialic acid
(with exception of
Zanamivir
Answer:
2.27 Zanamivir and Oseltamivir 235
Zanamivir is a stable a cleavable glycosidic bond.
Structurally identical
to N-acetylsialic acid
(with exception of
the double bond)
Glycosidic bond
Answer:
Lacks glycosidic bond
Zanamivir is a stable a cleavable glycosidic bond.
Zanamivir
The structural similarity allows zanamivir to interact withStructurally identical

neuraminidase in the same manner as
5. N-acetylsialic
Shown below acid.
is a activity is likely to be more active, less active,
to or similar
N-acetylsialic
Ionic or ion–dipole interactions with the carboxylic acid toremain
acid that of zanamivir?
the same, as does
(with exception of
the ability to form hydrogen bonds with the hydroxyl groups and the amide. Because zanamivir lacks
a cleavable glycosidic bond, it can occupy the binding site without the double bond)
being metabolically transformed.
The most significant difference between zanamivir and N-acetylsialic acid is the substitution of a
secondary hydroxyl group with a guanidine group. Studies have shown that this basic functional
group can form ionic interactions with neuraminidase. In summary, zanamivir structurally mimics the
natural substrate for neuraminidase and is able to bind to the active site of the enzyme. This binding
inhibits the ability of neuraminidase to cleave N-acetylsialic acid from viral glycoproteins, thus inhib-
iting the spread of a viral infection. Lacks glycosidic bond
Zanamivir
5. Shown below is a stereoisomer of zanamivir. Identify if the stereoisomer is an enantiomer, a diastereomer,

5. aShown belowisomer,
geometric is a activity
an epimer, to be more
is likelyand/or active, less active,
a conformational similarwhether
isomer.orPredict to that ofthis
zanamivir?
stereoisomer’s
pharmacological activity is likely to be more active, less active, or similar to that of zanamivir?
6. Shown below is the structure of for oseltamivir
Answer
6. This stereoisomer
Shown below is thehas the opposite
structure stereochemical configuration at all five chiral centers and has the
of for oseltamivir
exact same conformation as zanamivir; therefore, this is the enantiomer of zanamivir. None of the
other stereochemical designations are correct.
Given that zanamivir as well as oseltamivir exert their antiviral activity by mimicking N-acetylsialic
acid, alteration of the stereochemistry decreases the resemblance to N-acetylsialic acid and would be
predicted to cause a decrease in binding affinity to neuraminidase and a decreased antiviral effect.
6. Shown below is the structure of oseltamivir and a list of five metabolic transformations. For each
Chapter2.27
metabolic transformation, indicate if it is a phase I or a phase II transformation and if oseltamivir has
a functional group present that can undergo the indicated transformation. When evaluating these
PleasereplacethestructurefortheanswerofQ1withtheonebelow.
metabolic transformations, consider functional groups that are initially present within the structure
of oseltamivir as well as those that can be added/revealed through phase I metabolism. If you answer
YES, then draw the appropriate metabolite; if you answer NO, then provide a brief explanation as to
why this metabolic transformation is not possible for oseltamivir.
w is the structure of for oseltamivir
Carboxylic acid (Acidic functional group)

Normal pH range = 2.5 to 5
Metabolic Pathways
A. Hydrolysis Guanidine (Basic functional group)
B. Allylic oxidation Normal pH range = 12 to 13
C. Glucuronide conjugation
D. ω-Oxidation
E. Oxidative O-Dealkylation
Answer
Answer:
Please replace the structure for the answer to Q6, part a with the one below (page 4, middle structure)
a. Hydrolysis: Phase I transformation. Both the ester and amide functional groups can undergo
A. Hydrolysis: Phasehydrolysis
hydrolysis. Ester I oseltamivir.
produces the active metabolite of oseltamivir.
Product of Product of Product of ester

esterEster hydrolysis
hydrolysis Amide
amide hydrolysis
hydrolysis and Ester
amideand amide
hydrolysis
hydrolysis
b. Allylic oxidation: Phase I transformation. It is not possible because both allylic carbon atoms are
B. Allylic
alreadyoxidation:
attached Phase a hydrogenAdditionally,
to heteroatoms. atom that is required for carbon
one allylic oxidation.
atom lacks a hydrogen atom
that is required for oxidation.
Already attached
to a heteroatom
Lacks a hydrogen atom
Already attached
to a heteroatom Oseltamivir
C. Glucuronide conjugation: Phase II.

Already attached
to a heteroatom Oseltamivir
2.27 Zanamivir and Oseltamivir 237
C. Glucuronide conjugation: Phase II.

c. Glucuronide conjugation: Phase II transformation. It can occur directly with the secondary amine
or with the carboxylic acid that results from phase I ester hydrolysis.
D. Oxidation: Phase I, Yes
D. Oxidation: Phase I, Yes

d. ω-Oxidation: Phase I, Yes
E. Oxidative O-Dealkylation: Phase I, Yes

e. Oxidative O-Dealkylation: Phase I, Yes
E. Oxidative O-Dealkylation: Phase I, Yes
+
Index
A Angiotensinogen, 27, 129 C

Anticholinergic agents, 18, 114-115
Acebutolol, 21, 117-119 C-11 oxidation, 58, 179
Antidiabetic agent, experimental, 7-8, 99,
Acetylcholine, 79-80, 218-219 101, 102 C-17 oxidation, 58, 179
Acetylcholinesterase inhibitor, 79-81, Antihistamine, 39, 149-152 C-21, 60, 179-180
218-221 Cahn-Ingold-Prelog (CIP) system, 22,
Anti-hyperlipidemic agents, 47, 165
Acidic functional group, 7-9, 11-12, 31, 36, 119-120, 184
40, 55, 66, 69, 75, 81, 91, 99-103, Anxiolytic effect, 53, 172
Carbamate group, 81, 219-220
105-106, 137, 151, 155, 174, 190, Arformoterol, 13-14, 109
Carboxylic acid, 73, 185, 194, 206
193-194, 211-212, 233 Argatroban, 9, 103
Cefamandole, 21, 117-119
Action Arginine, 8, 102
Cefotaxime, 11, 105-106
duration of, 81, 220 Aripiprazole, 31-33, 137-142
Cefprozil, 35-38, 143-147
onset, 66, 190 metabolites, 33, 141
Cephalosporin, 35, 143
Active metabolite, 63, 186-187 Aromatic oxidation, 70, 141, 197
Cetirizine, 39-40, 149-152
Active product, 58-59, 179 Aspartic acid, 88, 98, 228
Chemical hydrolysis, 147
Adenosine triphosphate (ATP) binding, 87, Atenolol, 11, 105, 105-106
227 Chiral carbon atom, 62, 184
Atrial fibrillation, 43, 159
Administration routes, 14-15, 109-110 Chiral centers, 21-22, 119
Chlorimipramine, 24, 124
Alanine, 87, 227 B
Alendronate, 15, 111 Chlorpropamide, 41-42, 153-157
Baclofen, 13-14, 24, 109, 129
Aliskiren, 27-30, 129-135 Ciprofloxacin, 13-14, 109
Barbiturates, 71-72, 199-203
Allylic oxidation, 92, 236 Class IB anti-arrhythmic agent, 65, 189
Barbituric acid, 199
Alprazolam, 53, 172 Clonidine, 8, 102-103
Basic functional group, 7-9, 11, 12, 31, 36,
Amiloride, 9, 103 CNS-based toxicities, 67, 192
40, 55, 69, 75, 91, 99-103, 105-106,
Amino acid binding interactions, 32, 139-140 137, 144, 151, 155, 174, 193-194, Conformational isomer, 92, 235
Amino acid side chain interactions, 30, 44-45, 211-212, 233 Conjugate elimination, 48, 168
56, 58, 72, 88, 134, 163, 175, 178, Benzodiazepines, 53, 172 Cucumber flavor, 20, 116
201-202, 228-229, 230 Benzylic oxidation, 56, 70, 141, 176, 191, Cysteine, 88, 228
Amino acid-based hormone, 62, 185 198 Cysteinyl leukotriene receptors, 70, 196
Amino acids, 5, 98 Beta-lactam bond instability, 38, 147
Amlodipine, 30, 134-135 Beta-lactamases, 38, 147 D
Amphoteric drug, 9, 36, 103, 144 Binding interactions, 56, 175
Dabigatran etexilate, 43-45, 159-164
Anesthetic, 65, 189 Bioavailability, 132
mesylate, 45, 164
Angiotensin converting enzyme, 27, 129 Biological targeting, 14-15, 19, 110, 115
Dehalogenation, 61, 63, 183, 186-187
Angiotensin converting enzyme (ACE) Blood soluble, 65, 190
Delapril, 17, 113
inhibitor(s), 17, 75-78, 113, 211-215 Bromfenac, 3, 7-8, 37, 99, 101, 102
Depot injections, 60, 180
Angiotensin I, 27, 77, 129-130, 213 Butabarbital, 71, 199-200
Dexfenfluramine, 24, 125
Angiotensin II, 27, 129-130 metabolite, 72, 202-203
Diastereomer(s), 21, 28, 52, 62, 92, 117-119,
Angiotensin II receptor blockers (ARBs), 41,
130-131, 170, 184, 235
153
239
Dihydropyridine calcium channel blocker, Fluvoxamine metabolites, 53, 171 I

30, 134 Functional groups, 3-9, 11, 95-98, 99
Diltiazem, 9, 103 Ibuprofen, 4, 96
Imipramine analogs, 5, 97
Dipeptidyl peptidase IV, 83, 223 G
Dipole-dipole interaction, 202 Inactive metabolite, 63, 186-187
GABAA, 71, 72, 199, 201, 203
D-Phe-Pro-Arg tripeptide sequence, 43-45, Inactive product, 58-59, 179
Gemfibrozil, 47-49, 165-168
159-163 Induction, 4, 55, 79, 96, 173-174, 217
Geometric isomer(s), 21, 28, 52, 62, 92,
Drug action Inosinic acid, 20, 116
117-119, 130-131, 170, 184, 235
duration, 60, 181 Insulin, 62, 185
GI drug absorption compartments, 36, 145
stereochemistry and, 21-22, 117-121 structure, 14, 111
Glucocorticoid, 57-58, 177-178
Drug binding interactions, 17-20, 113-116 Interactions, 62, 185
Glucuronide conjugation, 53, 92, 172, 237
Drug interaction, 32, 139 Intermediate-acting agent, 71, 200
Glutamate, 20, 116
Drug metabolism, 23-24, 123-125 Intestine pH, 14, 109
Glutamic acid, 20, 79, 116, 218
Ion channels, 20, 116
Glutamine, 98
E Glyburide, 42, 158
Ion-dipole interaction(s), 19, 58, 62, 115,
185, 178
E-geometric isomer, 170 metabolite, 42, 158
Ionic bond, 202
Electron donation, 4, 55, 79, 96, 173, 217 Gram (-) activity, 35, 143
Ionic interaction, 62, 185
Electron withdrawing, 4, 55, 79, 96, 97, Gram (+) activity, 35, 143
173-174, 217 Ionization percentage, 12, 106-108
Green pepper flavor, 20, 116
Elimination, 48, 167 Ionized, 31, 36, 55, 69, 71, 75-76, 91, 137,
Guanidine functional group, 8, 102 145, 174, 193-194, 201, 211-212, 233
half-life, 49, 168
Irbesartan, 13-14, 109
unchanged, 70, 197 H Isoleucine, 87, 227
Embeconazole, 15, 111-112
Half-life, 42, 156
Enantiomer(s), 21-22, 52, 62, 92, 117-121,
170, 184, 235 Halogenated aromatic hydrocarbon, 185 L
Enterohepatic recycling, 23, 123, 124 Haloperidol, 55-56, 173-176 Leu-Val peptide bond, 30, 134
Enzymatic hydrolysis, 147 Henderson-Hasselbalch equation, 12, Levothyroxine (T4), 61-63, 183-187
106-107, 108, 155
Epimer, 92, 235 metabolites, 63, 186
Hepatic metabolism, 70, 197
Ester hydrolysis, 79-80, 218-219 Lidocaine, 65-67, 189-192
Hepatic oxidation, 53, 172 Sodium channel blocker, 65, 189-192
Estradiol, 21, 23, 117-119, 123
Heroin, 23, 123 Lipid solubility, 31, 138, 195
Estrogen, 62, 185
Histidine, 79, 218 Lipid soluble esters, 174
Ether, 185
HMG CoA reductase, 74, 207-209 Lipophilic absorption, 66, 190
Ezetimibe, 11, 105-106
HMG-CoA reductase inhibitor, 22, 119-120 Lipophilic ester, 60, 180-181
Hormone replacement therapy, 62, 184
F Lisinopril, 17, 113
Hydrochloride monohydrate salt, 89, 231 Lomitapide, 9, 103
Fenofibrate, 47-49, 165-168
Hydrochloride salt, 13-14, 109 Long-acting agent, 71, 200
as active drug, 48, 166
Hydrocortisone, 57-60, 177-181 Loperamide, 14, 109-110
as prodrug, 48, 166
Hydrogen bond(s), 18-19, 58, 62, 88-89, Lorazepam, 53, 172
Fesoterodine, 18, 114, 115 115, 178, 185, 195, 202, 207, 228
Losartan, 32, 41, 139, 153
Fibrin, 43, 159 Hydrolysis, 56, 70, 92, 176, 198, 236
L-tyrosine, 62, 185-186
Fibrinogen, 43, 159 Hydrolytic reactions, 44, 161-162
Flavors, 20, 116 Hydrolyzable peptide bond, 30, 134 M
Fluvastatin, 22, 73-74, 119-120, 205-209 Hydrophilic reaction, 4, 55, 73, 75, 79, 96,
conformationally restricted analog of, 173, 205, 211, 217 Maleate salt, 52, 170-171
74, 208-209 Hydrophobic reaction, 4, 19, 55, 62-63, Mechanism of action, 42, 155-156
Fluvoxamine, 24, 51-53, 125, 169-172 73, 75, 79, 88-89, 96, 114-115, 173, Metabolic transformation, 28-29, 53, 77-78,
metabolites, 53, 171 185-186, 196, 202, 205, 211, 217, 171-172, 214-215
228, 231 Metabolites, 24, 124
Fluvoxamine + alprazolam, 53, 172
Hydroxyzine, 39-40, 149-152 Methionine, 89, 230
Fluvoxamine + lorazepam, 53, 172
Index 241
Methylation, 70, 197 Phenol, 185 Serotonin receptor modulator, 31, 137
Mevalonic acid, 74, 207-208 Phenylalanine, 88, 228 Serotonin reuptake transporter (SERT), 51,
Montelukast, 69-70, 193-198 Phenytoin functional groups, 3, 37 169
Morphine, 23, 123 Phosphate salt, 84, 224 Serotonin selective reuptake inhibitors
(SSRI), 51, 169
pKa, 71, 201
N range, 6, 31, 73, 75-76, 91, 101-102,
Shitaki mushrooms, 20, 116
137, 206-207, 211-212, 233 Short-acting agent, 71, 200
N-acetylsialic acid, 91-92, 234-235
values, 42, 69, 154-155, 193, 194-195 Sitagliptin, 83-85, 223-226
Natamycin, 12, 106-107
Plasma pH, 11, 14, 105, 109 Sodium salt(s), 70, 71, 195, 200
N-dealkylated monoethylglycinexylidide,
67, 192 Plasma protein binding, 30, 32, 41-42, 70, Solubility, 13-15, 109-112
Neostigmine bromide, 81, 219-220 84, 134-135, 139, 153, 197, 225 Sorafenib, 87-89, 227-231
Nerolidol, 19, 115 Potassium salt, 13-14, 109 Sorbinil, 7-8, 99, 101, 102
Neuraminidase, 91, 234-235 Pravastatin, 9, 73-74, 103, 205-209 Stereochemistry, drug action and, 21-22,
Primarily ionized, 11, 105-106 117-121
Nifedipine, 21, 117-119
Primarily unionized, 11, 105-106 Steroid-based hormone, 62, 185
Nilotinib, 88-89, 229, 231
Primary amine, 185 Stomach pH, 11, 14, 105, 109
Nitrofurantoin, 11, 105-106
Prodrug(s), 44, 48, 60, 76, 161-162, 174, Sulfamethoxazole, 4, 96
Nonelectrolyte, 9, 103
180-181, 212 Sulfate conjugation, 23, 56, 123, 176
Non-hydrolyzable hydroethylene, 30, 134
Protein tyrosine kinases, 87-89, 227-231 Sulfonamide, 194
Non-peptidomimetic prodrug, 44, 161
Pyridyl nitrogen, 89, 230 Sulfonylureas, 41-42, 153-157
Norepinephrine reuptake, 24, 125
Nucleophilic side chain, 38, 147
Q T
O Quinapril, 75-78, 211-215 Taste receptors, 20, 116
Quinaprilat, 76-77, 212-213 Tetracycline, 13-14, 109
Odorant molecules, 19, 115
Tetrapeptide side chains, 5, 98
Oral anticoagulant, experimental, 7-8, 99,
101, 102
R Thrombin active site, 43, 159
Oral bioavailability, 52, 171 R-A double bond reduction, 58, 179 Thrombin inhibitor, 43, 159
Oseltamivir, 91-92, 233-237 Ranitidine, 12, 108 Thyroglobulin molecules, 61, 183
Oxidative N-dealkylation, 56, 142, 176 Reactions, 58-59, 179 Tocainide, 67, 192
Oxidative O-dealkylation, 48-49, 70, 92, Reduction, 56, 176 Tolbutamide, 32, 41, 139, 153-156
168, 198, 236, 237 R-enantiomer, 62, 84, 184, 224-225 Tolterodine, 18, 114-115
Oxidative transformation, 28-29, 132-133 Renin, 30, 134 Tolycaine, 67, 192
Oxybutynin, 18, 114-115 Resonance, 4, 55, 79, 96, 217 Tosylate salt, 89, 231
Ring A ketone reduction, 58, 179 Transformations, 58-59, 179
P Rivastigmine, 79-81, 217-221 Tricyclic antidepressant, 24, 124
Passive diffusion, 89, 231 Routes of administration, biological targets Tri-iodo-L-thyronine (T3), 61, 63, 183, 185
Penicillins, 38, 147 and, 14-15, 109-110 Tyrosine, 98
Peptide cleavage, 76, 213 Rule of Nines, 12, 69, 106, 194 Tyrosine kinase inhibitor, 87-89, 227-231
Peptide-based hormone, 62, 185
pH/pKa, 11-12, 105-106
S U
Phase I transformation, 23-24, 33, 37, Salmeterol functional groups, 3, 37 Umami receptor, 20, 116
40, 48, 53, 56, 66-67, 70, 72, 85, 92, Salts, 13-15, 109-112 Unionized, 31, 36, 55, 69, 71, 75-76, 91, 137,
123-125, 141-142, 146, 150-151, Scents, 19, 115 145, 174, 193-194, 201, 211-212, 233
167-168, 172, 175-176, 191-192,
Sclareol, 19, 115 Urinary pH, 11, 105
197-198, 202, 226, 236-237
Scopolamine, 14, 109-110
Phase II transformation, 23, 33, 37, 40, 48,
56, 70, 72, 92, 123, 125, 141, 146, Secobarbital, 71, 199-200, 201 V
151, 167-168, 175, 197, 202, 236-237 metabolite, 72, 202-203 Valine, 87, 98, 227
Phenobarbital, 71-72, 199-203 S-enantiomer, 62, 184 Van der Waals, 19, 87, 114-115, 140, 196,
metabolite, 72, 202-203 Serine, 79, 80, 218-219 202-203, 227
Vanillin, 19, 115

Vascular endothelin growth factor 2, 87,
227
W
Warfarin, 3, 37, 84, 225
Water solubility, 31, 138, 195
Water soluble ester, 60, 180-181
ω-oxidation, 92, 236, 237
Z
Zafirlukast, 69-70, 193-198
Zanamivir, 91-92, 233-237

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Marc W. Harrold, PhD

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© 2015, American Society of Health-System Pharmacists, Inc. All rights reserved.

To our students, whose

Preface .......................................................................................................................................................................................... vii

Section 2 Whole Molecule Drug Evaluation

2.3 Solving pH/pKa Problems................................................................................................................................................ 105

Section 4 Whole Molecule Drug Evaluation

INDEX .................................................................................................................................................................................... 239

7. Spatial orientation of functional groups

8. Metabolic routes of drug activation, inactivation, and/or elimination

Section 1 - General Self Assessment

Structures for 1.1 and 2.1 1.1 Functional Group Characteristics

copies in the event you wanted that.

Box Functional Group Name

Box Hydrophilic or Hydrophobic

1.1 Functional Group Characteristics and Roles 5

Analog A Analog B Analog C

four amino acids have been boxed.

1.2 Identifying Acidic and Basic

Experimental oral anticoagulant Bromfenac

Drug Name Experimental oral anticoagulant

Experimental Antidiabetic Agent

Drug Name Basic Functional Group Experimental

Drug Molecule Acid/Base Character of Drug Molecule

1.3 Solving pH/pKa Problems

Drug (pKa Value) Stomach (pH=1.8) Urine (pH=6.1) Plasma (pH=7.4)

The pKa values for natamycin are 4.6 and 8.4.

1.4 Salts and Solubility

Name of Functional Is the Potassium Name of Functional Is the Hydrochloride

Biological Targets and Routes of Administration

Insulin Structure PO3Na2

S S H2N PO3Na2 A Chain

1.4 Salts and Solubility 15

4. Based on your structural evaluation of embeconazole, answer the following questions:

Can it be formulated as:

a. a topical ointment or cream? YES NO

1.5 Drug Binding Interactions

Sclareol Vanillin Nerolidol

Glutamic Acid Cucumber flavor Green Pepper Flavor

Glutamic Acid Cucumber flavor Green Pepper Flavor

compounds, identify all chiral centers.

2. For each of the four drug molecules shown in question 1:

Drug Metabolism 1.7 Drug Metabolism

CF3 Dexfenfluramine CF3

Section 2 – Whole Molecule Drug

1.21 Phenobarbital and Other Barbiturates......................... 71

28 Medicinal Chemistry Self Assessment

Missing diagram for Question #4 (Chapter 1.8/2.8)

Name of Metabolic Transformation Oxidative or Non-Oxidative

5. Assume that at a physiological pH of 7.4.

32 Medicinal Chemistry Self Assessment

1. Conduct a complete structural evaluation

Ionized or Ionized or Ionized or

Name of Transformation Phase I or Phase II

Ionized or Ionized or Ionized or

1.12 Chlorpropamide and

1.12 Chlorpropamideand Other Sulfonylureas