CHIRAL PHARMACOLOGY

Md akbar M Pharm (Pharmacology) 2nd semester Jamia Hamdard New Delhi

Introduction
In simple terms,chirality is handedness-that is ,the existance of left/right opposition.for example,our left and right hand are mirror image but cant be superimposable and therefore they are chiral(enantiomer) The term chiral was coined by Lord Kelvin. While the concept of asymmetry were developed by J.h.vant Hoff and j.a. le bel in 1874 followed by louis Pasteur.

Enantiomer
These are compounds that have the same molecular
formula and the same funtional groups bonded in thesamefashion,butwhich differ in the three dimensional (3d)arrangement of their atoms or group. Chiral compound should have at least one asymmetric carbon atoms in the molecule. A carbon atom is said to be asymmetric if it has four different atoms or group attached to it . If chiral molecules are mutually mirror image and nonsuperimposable Such space isomers are known as enantiomer .A synonym is antipodes.

Enantiomer (two form of chiral)

Diastereomers
Diastereomers are compounds that are nonsuperimposable, nonmirror image isomers such compound has more than one chiral center in the molecules.

These isomers have different physical and chemical properties and thus differences in biological activity between such isomers for example, Epedrine and pseudoephedrin

A
Diastereomers

Enantiomers

Diastereomers

Enantiomers

Racemic mixtures
A mixture of equal amounts of two enantiomers
that is (+) and (-) forms is called a racemic mixture such a mixture is optically inactive(doesnt rotate the plane of polarised light ) b/c the two component rotate the plane of polariged light equally in opposite directions and canceal one another.

For example, (+/-)Lactic acid

STEREOCHEMICAL TERMINOLOGY
There are different systems to classify them The first system of stereoisomer nomenclature is the d/l or (+)/-) system that is based on the direction in which the compound rotates planepolarized light. Enantiomers that rotate plane-polarized light to the right are termed as dextrarotatory which is indicated by d- or (+) and those that rotate light to the left are termed as levorotatory and are designated by a l- or (-)prefix. A racemic mixture is indicated by either a d/l- or (+)/(-)-prefix. This system has been used in chemistry for a long time, but the rotation of plane-polarized light is not an absolute property . It is generally known that the rotation depends on the solvent used For example, chloramphenicol is dextrarotatory in alcohol but levorotatory in ethyl acetate .

Contd.

 The second and current system of stereoisomers is based on the sequence of atoms or groups around its chiral centre . It is known as the Cahn- Ingold-Prelog system or (R,S)system .It is the only system permitted to describe the absolute configuration of compounds which have more than one chiral centre.
Groups of atoms attached to the chiral centre are arranged according to a sequence rule, in priority order of decreasing atomic number. I > Br > Cl > F > OH > NH2 > CH3 > H If the order of decreasing priority of the groups forming the triangle is clockwise, then the configuration is called Rwhich stands for rectus. If the order of decreasing priority of groups is counterclockwise, then the configuration is called S- which stands for sinister .

CHIROTECNOLOGY
The process has been re-explored in recent years focusing on
the development of the target specific drugs through the approach of enantiomeric drugs. Based on the pharmacological aspects of the drug and the receptor complexation,. Trends in the pharmaceutical markets predict magnanimous growth in single enantiomer drugs over racimates. Worldwide sales of chiral drugs as single enantiomers are showing steady growth at an average of 13 percent . The prediction of the market shows substantial growth for the market of the chiral drugs and sales estimates are made up to $200 billion by 2008.

CHIRALITY and PHARMACOLOGY

In pharmacology, chirality is an important factor in drug efficacy.

About 56% of the drugs currently in use are chiral compounds, and among them about 88% of chiral synthetic drugs are used therapeutically as racemates.It means only 12% drugs are marketed as pure single enantiomers ,so that we have to try to development of rest of racemates in a single enantiomers.
Unfortunately, there are many racemic drugs where the stereospecificity of the metabolism and/or the pharmacodynamic effects of the enantiomers is not known

EFFECT OF CHIRALITY ON PHARMACOLOGICAL ACTIVITY

The drug interaction hypothesis was proposed by Beckett

The differences in biological activity b/w enantiomers depends on their ability to react selectively at the receptor site In case of epinephrine ,only (-) isomer has the -OH group in the correct orientation to allow perfect binding with receptor
This explanation has been proposed as the reason for high pressor activity of (-) epinephrine ,whereas the (+) form of epinephrine shows less activity.

Pharmacokinetic and Pharmacodynamic implications of chirality

All the pharmacokinetic processes, viz, absorption, distribution, metabolism and excretion may be influenced by chirality. for e.g., esomeprazole is more bioavailable than racemic omeprazole. The volume of distribution of levocitrizine has been shown to be smaller than that of its dextro form , which is a positive aspect in terms of both safety and efficacy. Drug metabolizing enzyme systems are also subject to stereos elective influences. Two isomers of a drug are often metabolized at different rates. This may result in accumulation of the inactive enantiomer or rapid elimination of the active one and vice versa.

Eudismic Ratio
Terminology applies to a particular activity of a drug. Dual action drug the Eutomer of one activity may be the Distomer for another. Propranolol: S-enantiomer 40-100 fold more potent than the R- as a -adrenoceptor antagonist; similar activity with respect to their membrane stabilising properties. Eudismic Ratios may also vary with receptor subtypes. Noradrenaline: ER (R/S): 1, 107; 2, 480. -Methylnoradrenaline: ER (1R,2S/1S,2R): 1, 60;2, 550.

The pharmacodynamics implications of the concept of chirality in drug activity stem from the fact that the beneficial effects of a drug can reside in one enantiomer. Its counterpart enantiomer having either no activity or less activity or antagonist activity against the active enantiomer or completely separate beneficial or adverse activity from the active enantiomer.

The active and inactive enantiomers are referred to as eutomer and distomer respectively

Chiral switches
It involve development of single enantiomer from racemic drug which is already marketed. For example escitalopram, esomeprazole, dexibuprofen, dexketoprofen, S-Ketamine , laevocetirizine, laevofloxacin, (R, R)-methylphenidate, laevoleucovorin, levo-bupivacaine, and eszopiclone are the examples of chiral switches because these drugs were initially marketed as racemic mixtures. Some of the chiral switches under development are: Dexloxiglumide, S-Doxazosin, R- and S- fluoxetine, Rlipoic acid , S-oxybutynin and Dexnorcisapride.

SINGLE ENANTIOMER AND ITS ADVANTASES

S-amlodipine CCB, long half-life , less metabolic load, and negligible pedal edemas. S-atenolol beta-1 blocker, and lesser side-effects on switch-over from racemate to eutomer. S-metoprolol, - avoiding the beta-2 blocking component, safer in poor metabolisers of CYP2D6, and avoids many drug-drug interactions. S-pantoprazole more potent PPI and cytoprotective R-ondansetron Clinically more potent component, does not prolong QTc interval, safer in children and elderly, and lesser side-effects racemate in poor metabolisers All the above single enantiomer need half the racemate dose.

A chiral HPLC-column for direct resolution of enantiomers

CHIRAL-AGP is alpha1-acid glycoprotein (AGP). This is very stable protein. That tolerates high concentrations of organic solvents, high and low pH, and high temperatures. The column is used in the reversed-phase separates enantiomers of an extremely broad range of drug compounds: amines (primary, secondary, tertiary, and quaternary) acids (strong and weak) nonprotolytes (amides, esters, alcohols, sulphoxides, etc.)

Application Areas of chiral AGP

At pharmaceutical companies, hospitals, universities and chemical industry. CHIRAL-AGP is used for the analysis of enantiomer purity and for bioanalysis.

A growing application area is isolation of pure enantiomers on semipreparative columns.

Potential advantages of single enantiomer products

Less complex, more selective pharmacodynamics profile Potential for an improved therapeutic index Less complex pharmacokinetic profile Reduced potential for complex drug interactions Less complex relationship between plasma concentration and effect

TRENDS IN THE DEVELOPMENT OF CHIRAL DRUGS

Drug chirality is now a major theme in the design, discovery, development, launching and marketing of new drugs. Stereochemistry is an essential dimension in pharmacology. Worldwide sales of chiral drugs in single-enantiomer forms continue to grow.. The top ten single enantiomer blockbuster drugs (>US $1 billion sales per year) are: Atorvastatin calcium, Simvastatin , Pravastatin sodium , Paroxetine hydrochloride (CNS); Clopidogrel bisulfate , Sertraline hydrochloride , Fluticasone propionate and salmeterol xinafoate ; Esomeprazole magnesium , Amoxicillin and Valsartan .

Recent Chiral Trends: USA

50 45 40 35 30 25 20 15 10 5 0 2004
[[

Achiral Chiral Racemic Chiral Single Stereoisomer Others (peptides, proteins, polymers etc) 2003 2002 2001 2000

In 2006, 80% of small molecule drugs approved by the FDA were chiral and 75% were single enantiomers.

CHIRAL MOLECULES IN HYPERTENTION

Amlodipine exhibits chirality, i.e., it exists as two isomers. Moreover, the receptor binding studies have shown that the S (-) isomer of amlodipine that has L-type calcium channel blocking activity. The R (-) isomer exhibits a 1000-fold weaker calcium channel blocking activity. Thus, the antihypertensive and antianginal activity of amlodipine can be attributed only to S (-) amlodipine, whereas the R (-) isomer can be regarded as inactive. S (-) component is found to produce vasodilation by blocking the calcium channels in the arterial circulation. This property contributes to its antihypertensive effect. On the other hand R(+) isomer produces venodilation and is responsible for the side effects associated with racemic amlodipine.

Some drugs are developed as pure enantiomers

Defined as new single isomer chemical entity (NSCE) such as enalapril, ramipril, diltiazem, atorvastatin, simvastatin, pravastatin, clopidogrel, L-carnitine, laevodopa, d-penicillamine, levetiracetam, and rivastigmine.

R- PROPRANOLOL

S- PROPRANOLOL

HN R OH H

HO H O

HN S

Chiral inversion
Chiral inversion is conversion of one enantiomer into its mirror image. For example, the S form of ibuprofen is active but significant R (inactive enantiomer) to S inversion takes place in the body.

Harmful intermediates are released during R-toS conversion upon administration of racemate. whereas administration of S-ibuprofen results in no such release of intermediates . This is thought to be the reason of enhanced safety of S-ibuprofen over the racemate.

Racemic Omeprazole is a very potent inhibitor of gastric acid secretion. omeprazole exhibits polymorphic metabolism, in a few individuals (3% among the Caucasian populations and 15-20% among Orientals) that metabolize omeprazole slowly (slow metabolizers)as compared to the rest of the population (rapid metabolizers), AstraZeneca developed the chiral switch drug esomeprazole (which is the (S)-(-)-enantiomer of omeprazole) based on the therapeutic benefit would be achieved by less inter-individual variation, (slow versus rapid metabolizers), and that average higher plasma levels would provide higher dose efficiency in patients . Esomeprazole was introduced as the magnesium trihydrate salt first in Europe under the now famous trade name Nexium.

Pharmaceutical industry's role in chiral switches

Pharmaceutical companies are in the forefront of pharmaceutical research and are responsible for providing chirally pure products for clinical use. However, the acceptance of any molecule (including chiral switches) would depend on its advantages . Launching of chirally pure products from the racemate that has been already promoted requires considerable amount of time and monetary investments on its chemical separation and clinical evaluation.

REFERENCES
www.japi.org VOL. 52 MARCH 2004 J Indian Med Assoc 2007; 105: 177-8 J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 4(2):185-200, 2001 www.drugdiscoverytoday.com www.leffingwell.com Journal of Applied Biomedicine 2: 95.100, 2004 www. Express pharma pulse http://www.indianjmedsci.org www.fda.gov/cder/guidance/stereo.htm. W.O.FOYE, principles of medicinal chemistry, 5th edition, www.pubmed.gov Indian Journal of Pharmacology 2006; 25: 73 77.