Discussion

Dr. Prashant ShuklaJunior ResidentDept. of PharmacologyGMC Patiala

Enantiomers

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Chiral compounds possess the property

of handedness May be right-handed

or left-handed

Achiral object exists only in one form

No possibility of left- or right-handedness

Chemical Compounds

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Pictorial representation

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IntroductionEnantiomers are optical isomers which are

non superimposable mirror-like image structures. AKA Enantiomorphs.

Enantiomers can be distinguished by their ability to rotate a beam of plane-polarized light: ◦to the clockwise direction as a dextrorotatory

(+)-enantiomer ◦to the counterclockwise direction as a

levorotatory (-)-enantiomer. ◦A mixture of equal portions (50/50) of the (+)

and (-) enantiomers is called a racemic mixture.

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The majority of racemic pharmaceuticals have one major bioactive enantiomer (called eutomer).

The other is inactive or less active (distomer) or toxic or can exert other desired or undesired pharmacological properties.

Eudysmic ratio: The diff. in pharmacologic activity between the two enantiomers of a drug.

An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form.

Introduction

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OPTICAL ISOMERSPoints of similarity Points of difference1. Melting point,

boiling point, density.

2. pKa3. Solubilities

1. Rotation of polarised light

2. Odor, enzyme activity

3. PK/PD parameters

Introduction…

DEXTRO-ROTATARY

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Naming ConventionsThe optical isomers are named:By configuration: R- and SBy optical activity: (+)- and (−)-

or d- and l-By configuration: D- and L-

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Importance of enantiomers

(-)(S)-thalidomide (+)(R)-thalidomide

Effective sedative Teratogenic

The thalidomide tragedy forced drug companies to reconsider enantiomers as separate molecules rather than just different forms of the same drug.

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FDA recently recommends the assessments of each enantiomer activity for racemic drugs in body and promotes the development of new chiral drugs as single enantiomers.

A “chiral switch” occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version.

Importance of enantiomers...

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Enantiopure drugs

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Pharmacological classificationGroup I . Racemic drugs with one major

bioactive enantiomer:1. CCBs such as verapamil, nicardipine,

nimodipine,etc, except diltiazem.2. All ACE inhibitors such as captopril,

benazepril,enalapril, idapril.3. Anticonvulsants such as mephenytoine,

ethosuximide.4. Antiarrhythmics and local anesthetics such as

propafenone, disopyramide, prilocaine, tocainide.

5. Antibiotics such as ofloxacin, moxalactam; 6. Anticoagulants such as warfarin,

acenocoumarol;

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7. Antihistaminics such as terfenadine, loratadine; 8. Antihyperlipidemic such as atorvastatin; 9. Psychostimulants such as amphetamine,

metamphetamine10. PPIs such as omeprazole, pantoprazole,

lansoprazole

Group 2. Racemic drugs with equally bioactive enantiomers: Cyclophosphamide (antineoplastic), flecainide (antiarrhythmic), fluoxetine (antidepressant)

Group 3. Racemic drugs with chiral inversion

Pharmacological classification…

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PK parameter

Examples

Absorption

1. L-Methotrexate is better absorbed than D-Methotrexate

2. Esomeprazole is more bioavailable than racemic omeprazole

Vol. of distribution

1. S-Warfarin has lower Vd than R-Warfarin.

2. Levoceterizine has smaller Vd than its dextroisomer.

Metabolism

S-warfarin is more potent and metabolized by ring oxidation while R- Warfarin is less potent and metabolized by side chain reduction

Half-life S-warfarin= 32 hours; R-warfarin= 54 hours

PK implications of chirality

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PD implications of chirality

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PD parameter

Examples

Potency 1. S-Timolol is more potent α-blocker than R-Timolol.

Differential actions

1. L-Sotalol is β-blocker while D- Sotalol is not.

2. R(-)-Carvedilol is non-selective β-blocker while both S(+) and R(-)-Carvedilol has α-blocking property.

3. D-(+) 2R,3S propoxyphene is analgesic while (-) 2S,3R propoxyphene has anti-tussive action.

4. L-Propanolol is β-blocker while D form is inactive.

PD implications of chirality…

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PD parameter

Examples

Differential actions

5. S-Ibuprofen is active form while R-Ibuprofen is inactive form.

6. Most β2 agonists are available as racemic mixtures. But only the R-isomer is has β-2 agonistic activity while S-isomer has no such activity. Ex: Salbutamol

7. Labetalol has two optical centres It has 4 isomersRRSR RS SS

PD implications of chirality…

INACTIVE

POTENT β -BLOCKERPOTENT α -BLOCKER

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Advantages1. Separating unwanted side effects if these

reside exclusively in one enantiomer.2. Reduce metabolic/renal/hepatic drug load.3. Easier assessment of physiology, disease

and drug co-administration effects.4. Reduce drug interactions.5. Avoid enantiomer–enantiomer drug

interactions.6. Easier assessment of efficacy and toxicity.

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Chiral inversionA metabolic process which requires enzyme activi

ty to convert one enantiomeric form  into the other. Metabolic enzymes can:

1. introduce a stereogenic centre into a non-chiral molecule to form enantiomeric metabolite

2. alter a ligand attached to a stereogenic centre with either retention or inversion of chirality

3. introduce an additional stereogenic centre into a chiral molecule to produce diastereomeric  metabolites

4. convert a pair of enantiomers into a common  metabolite by removal of a stereogenic centre

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There are two kinds of drug chiral inversion:

1. Unidirectional inversion: R-enantiomer can undergo chiral inversion by hepatic enzymes into the active S-enantiomer and notvice-versa

2. Bidirectional inversion: Bidirectional chiral inversion or racemization should be represented by 3-hydroxy-benzodiazepines (oxazepam, lorazepam, temazepam) and thalidomide.

Chiral inversion

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Chiral inversion…

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Regulatory considerationsA pure enantiomer developed from a

previously registered racemic drug should be submitted, treated, and evaluated as an application for a new drug to the formulary.

Therapeutic economic risk/benefit aspects of enantiomer versus racemate must be judged separately for each drug.

It may not be economically feasible to pay an increased amount for only slightly increased efficacy.

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Chiral separation/ Chiral resolutionChiral separation is a procedure used to

separate the 2 isomers of a racemic compound.

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ConclusionsChirality is now a top-class subject for

academic research as well as for pharmaceutical development.

Accounting for the important role of chiral separation, the 2001 Nobel Prize was awarded to Dr. W.S. Knowles, Dr. K. Barry and Dr. R. Nyori, for their development of asymmetric synthesis using chiral catalysts in the production of single enantiomer drugs.

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References1. Chhabra N, Aseri ML, Padmanabhan D. A

review of drug isomerism and its significance. Int J Appl Basic Med Res. 2013 Jan-Jul;3(1):16-18.

2. McConathy J, Owens MJ. Stereochemistry in drug action. Primary care companion J clin psychiatry.2003;5(2):70-73.

3. Leffingwell JC. Chirality & Bioactivity I.: Pharmacology Leffingwell Reports. May 2003;3(1).

4. Nguyen LA, He H, Huy CP. Chiral drugs: AN overview. Int J Biomed Sci. 2006;85-106.

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