Home : Chirality >> What is Chirality?
Stereoisomers are compounds made up of the same atoms connected by the same sequence of bonds, but having different three dimensional structures. Enantiomers are mirror image stereoisomers. A chiral object is not superimposable on its mirror image. Chiral molecules possess either: an asymmetrically substituted atom (mainly carbon) or other asymmetry elements imparting an overall chiral shape. The Cahn-Ingold-Prelog system is commonly used in designating the absolute configuration of a chiral compound as R (rectus) or S (sinister) isomers. Enantiomers can rotate the plane of the polarized light either in a clockwise direction (dextrorotatory/ (+)-enantiomer) or anticlockwise direction (levorotatory/ (-)- enantiomer). An equimolar mixture of R and S enantiomers is called a racemate.
Many pharmaceutical compounds are marketed as racemates. Some of them need to be used as racemates for optimum activity e.g. labetalol and nebivolol. Many racemates need to be separated into single enantiomers or chirally pure components prefixed as R or S enantiomers. It is demonstrated that each enantiomer by virtue of three dimensional structure can interact with binding sites of enzymes and receptors differently and one with strong binding provide pronounced pharmacological action. Hence the pharmacological differences caused by enantiomers can be pharmacokinetic or pharmacodynamic in nature.
The pharmacokinetic implications of chiral drugs are exemplified by the bioavailability of R-verapamil which is twice that of S-verapamil and attributed to the reduced hepatic first-pass metabolism, Similarly R-pantoprazole and R-metoprolol are subjected to much higher variability than their S-counterparts in extensive/poor metabolizers. Overall, the single enantiomer provide less complex pharmacokinetics, reduced metabolic load over the enzymatic system and finally, offer less interaction potential.
The pharmacodynamic 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.
Examples of drug candidates in which one enantiomer is ‘active’, while the other enantiomer is “inactive” are S-atenolol - beta blocking property resides in its S-form, levocetirizine – antihistaminic profile is associated with the R-enantiomer (levo) while the S-enantiomer (dextro) being essentially inactive; and levofloxacin – antibacterial activity resides in the S-enantiomer only.
Examples where one isomer is more potent than the other are (R, R)-methylphenidate - approximately ten fold more potent than (S, S)-methylphenidate; R-ondansetron - more potent than the S-enantiomer; S-pantoprazole - more potent than the R-enantiomer; and esomeprazole - more potent than the R-enantiomer.
Examples where beneficial effects reside in one enantiomer, the other enantiomer having antagonistic activity are: salbutamol whose bronchodilator activity resides with (S)-salbutamol, the latter is indirectly involved in antagonizing the benefits of (R)-salbutamol and may have proinflammatory effects; R-lipoic acid is responsible for most of the beneficial effects while the corresponding S-form can oppose the action of its R-form.
The literature indicates many examples where enantiomers have entirely different therapeutic possibilities. For example: R-fluoxetine is useful for depression while S-fluoxetine is envisaged for migraine treatment; S-propranolol has beta-blocking and membrane stabilizing property, its counterpart, R-propranolol, has membrane stabilizing and spermicidal properties and may be useful in hyperthyroidism; R-sibutramine metabolite is under evaluation for the treatment of depression while the S-sibutramine metabolite may be useful for the treatment of erectile and ejaculatory dysfunction. These possibilities need research, development, and validation.
Examples of beneficial effects in one enantiomer whilst the other enantiomer has adverse activity are: S-amlodipine is a calcium channel blocker (CCB) while R-amlodipine is inactive as CCB and is thought to be responsible for pedal edema observed with racemic amlodipine; the post-anaesthetic emergence reactions (hallucinations and agitation) are predominantly associated with R-ketamine and not with S-ketamine, the latter being used for dissociative anaesthesia; levo-bupivacaine is a safe drug while cardiotoxicity is predominantly associated with its R-enantiomer; beta-1 selectivity of S-metoprolol is similar to that of racemic metoprolol, while the R-enantiomer is almost non-selective and may cause adverse effects related to additional beta-2 blockade; S-oxybutynin has equivalent antispasmodic activity with lower incidence of antimuscarinic side-effects than seen with racemate oxybutynin.
As a result of the appreciation of differences between enantiomers, the USFDA (United States Food and Drug Administration) issued guidelines in 1992 and again in 1995. The guidelines strongly encourage the development of single isomers and discourage the commercialisation of racemic mixtures. Approval can not be granted for a drug containing more than one isomer unless the pharmacokinetic and pharmacodynamic properties of each could be described and, more importantly, justified.
Some drugs are developed as pure enantiomers and defined as new single isomer chemical entity (NSCE) such as enalapril, ramipril, diltiazem, atorvastatin, simvastatin, pravastatin, clopidogrel, L-carnitine, levodopa, d-penicillamine, levetiracetam, and rivastigmine. Chiral switches involve development of unichiral version of the racemic drug already marketed. For example escitalopram, esomeprazole, dexibuprofen, dexketoprofen, S-ketamine, levocetirizine, levofloxacin, (R, R)-methylphenidate, levo-leucovorin, 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, R-lipoic acid and S-oxybutynin.
Chiral switch has been proposed to be a means of obtaining safer alternatives to existing racemates. Switching from existing racemate to one of its isomers has provided safer alternatives to drugs ranging from antihistamines like cetirizine to anaesthetics like ketamine. Some recent chiral switches have yielded safer and/or more effective alternatives to the existing racemates. These include levosalbutamol, S-ketamine, levobupivacaine, S-zopiclone, levocetirizine, S-amlodipine, S-atenolol, S-metoprolol, S-omeprazole, S-pantoprazole, and R-ondansetron. More chiral switches are expected to replace the racemates with safer options, making drug therapy more effective and safer.
In India, Emcure Pharmaceuticals Limited, Pune has taken the lead in developing several single enantiomer (unichiral) drugs, e.g. S-amlodipine, S-atenolol, S-metoprolol, S-pantoprazole, and R-ondansetron. The advantages of these unichiral drugs are briefly enumerated below:
S-amlodipine: provision of the active CCB component only, longer half-life of S-isomer, consistent pharmacokinetics due to less inter-subject variability of S-isomer compared to R-isomer, half the racemate dose, less metabolic load, prevention of accumulation of R-amlodipine in elderly, negligible pedal edema, while retaining the ancillary properties of the racemate.
S-atenolol: provision of the active beta-1 blocker component only, half the racemate dose, and lesser side-effects on switch-over from racemate to eutomer.
S-metoprolol: provision of the beta-1 blocker component only, half the racemate dose, avoiding the beta-2 blocking component, can be administered at high doses without causing beta-2 receptor medicated side effects, safer in poor metabolizers of CYP2D6, and avoids many drug-drug interactions.
S-pantoprazole: provision of more potent PPI and cytoprotective component, half the racemate dose, consistent pharmacokinetics, safer than racemate in poor metabolizers, and lesser potential for drug interactions.
R-ondansetron: clinically more potent component, half the racemate dose, does not prolong QTc interval, safer in children and elderly, and lesser side-effects.
The success of unichiral products (expected sales = $200 billion by 2008), US FDA regulations and scarcity of blockbuster new entities indicate that in the foreseeable future the pharmaceutical industry will be placing increasing emphasis on the development of chiral drugs as single enantiomers and to carry out racemic switches in all areas of therapeutics. This will be significant step towards offering rational, safer and more effective therapies. Clearly, the future lies in chiral purity.
Further reading:
McConathy J and Owens MJ. Stereochemistry in Drug Action. Primary Care Companion J Clin Psychiatry 2003; 5: 70–73.
Hutt AJ, Valentová J. The chiral switch: The development of single enantiomer drugs from racemates. Acta Facult. Pharm Univ Comenianae 2003; 50: 7-23.
Patil PA, Kothekar MA. Development of safer molecules through chirality. Indian J Med Sci 2006; 60 (10): 427-37.
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