Učinkovine za zdravljenje ulkusa

• Antagonisti H2 receptorjev (npr. cimetidin, ranitidin,

famotidin)
• Zaviralci protonske črpalke (omeprazol, esomeprazol,
lansoprazol, pantoprazol,
rabeprazol)
• Antagonisti muskarinskih receptorjev (npr. pirenzepin)
• Prostaglandini (npr. misoprostol)
• Zaviralci gastrina (proglumid)
• Antacidi
• Sukralfat
Mehamizem izločanja klorovodikove kisline

Zaviralci gastrina

misoprostol

parietalna
celica
 Pirenzepin

O
H
N

N N

O glej seminar
Učinkovine z delovanjem
N na parasimpatik

N
CH3
Selektivni antagonist muskarinskih M3 receptorjev
 Proglumid
H3C

N O
H3C

HO - zaviralec gastrina
NH
- zaviralec holecistokinina
O
O

Gastrin
• gastrin I, gastrin II sta heptadekapeptida
• stimulirata izločanje kisline v želodcu
Gastrin I
PyroGlu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2
 Misoprostol

O
O
CH3
O
H3C OH
CH3

HO

misoprostol glej izbirni predmet

Eutomeri
za profilakso ulkusa pri terapiji z NSAID
Sukralfat
Mehamizem izločanja klorovodikove kisline

misoprostol

parietalna
celica
 H+/K+ - ATPaza

proti
gradientu

A general model of cation motive ATPases illustrating the cytoplasmic, membrane and extramembranal sectors. The dominant
region is the cytoplasmic domain, but transport occurs across the membrane domain as illustrated schematically.
 H+/K+ - ATPaza

A possible arrangement of the membrane segments

of a P2-type ATPase with the ion (blue sphere)
transport pathway largely enclosed by TM4, 5, 6
and 8.
 Inhibitorji protonske črpalke
OMe
H3C CH3
O N OMe
N S
Omeprazol 1988
N
OCH2CF3 H
CH3
O N
N S lansoprazol
N
H
OMe
OMe
O N OCF2H
N S pantoprazol
N
H
O(CH2)3OMe
CH3
O N
N S rabeprazol
N
H

piridin-2-ilmetil benzimiazol-2-il
sulfoksid
Omeprazol kot predzdravilo
 Razvoj omeprazola in esomeprazola
patentni
problemi!
Astra toksičnost,
1972 vgradnja v obroč (tuberkulostatik)

lipofilnost !!!
metabolit,
ni patentno hipertrofija ščitnice ne zavira
zaščiten atrofija timusa absorpcije joda

višji pKa
 Esomeprazole magnesium
Launched 2000

Esomeprazole magnesium (formerly known as perprazole), the (S)-enantiomer of the marketed

proton pump inhibitor omeprazole (Losec), has been developed by AstraZeneca as an improved
second-generation successor to Losec with several advantages over the first-generation
compound. Omeprazole has one significant known drawback: polymorphic metabolism.
Approximately 3% of all Caucasian patients and some 15-20% of Oriental patients metabolize
omeprazole more slowly than the general population. In slow metabolizers, plasma concentrations
of the drug are higher than the average. Since the inhibition of gastric acid secretion is correlated
to the plasma concentration AUC, these slow metabolizers experience a more pronounced effect
from the drug. As such, the search was initiated for an improved version of omeprazole with less
interindividual variation and that would produce higher plasma levels. The result of this search
was the discovery of esomeprazole, which proved throughout an extensive clinical testing
program to possess unique pharmacokinetic properties of esomeprazole that contribute to rapid
symptom resolution and high and predictable healing rates. AstraZeneca recently filed for
marketing approval of esomeprazole sodium (Nexium) in the U.S. and Europe. The drug is
targeted for the treatment of GERD, including reflux esophagitis, and for the healing and
prevention of relapse of Helicobacter pylori-associated duodenal ulcers.
 Ali je na vidiku
nov kiralni preklop (chiral switch)

TAP Pharmaceutical Products submitted a NDA in January 2008 to the US FDA for
the use of dexlansoprazole in the treatment of acid-related diseases and the treatment
and maintenance of patients with erosive oesophagitis and non-erosive reflux disease.
The submission was based on global studies in more than 20 countries; more than
6000 patients with erosive and non-erosive GERD were included in the trials 2.
Sinteza
omeprazola kalijev etilksantogenat

(I)
 ???
Sinteza
omeprazola
(II)

Polonovski-jeva
premestitev
Sinteza
omeprazola
(III)
Sinteza
omeprazola
(VI)
 Ti(OPr)4, H2O2, (-)-dietil D-tartrat
Penicillium frequetans

Rhodobacter capsulatus
Sinteza lansoprazola
Sinteza pantoprazola
Sinteza pantoprazola
Sinteza rabeprazola