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Chirality – Today and CHAPTER Tomorrow’S Way of Treatment 23 P Chirality – Today and CHAPTER Tomorrow’s Way of Treatment 23 P. Bhandari, C. Shah, S. Surwade Introduction as many fixed-dose combinations of different drugs An object is “chiral” if and only if it is not super we are aware of. imposable on its mirror image.1 “Chiral” refers to the The science of “chirality” includes the synthesis spatial orientation of objects including molecules. of single enantiomers, their intermediates and Molecules must interact with receptors, enzymes chiral “switches”. In a “chiral switch”, the more and binding sites for absorption, distribution, useful enantiomer is isolated from the mixture metabolism, excretion and action. This interaction (racemate) and presented as an improved single is stereospecific and depends on how closely the enantiomer chemical entity. The term “unichiral” three dimensional structure interacts or fits onto the is recommended to be used to specify the three dimensional receptor or binding site.2 Thus stereochemical composition as stereochemically similar looking mirror images may not behave in homogeneous, i.e., consisting of a single-enantiomer. same manner with respect to such binding sites. The word “homochiral” has also been used to mean Just as one would not wear a right shoe on the left “unichiral”.1 foot or a right handed person would not try to write with the left hand, the orientation of molecules is Why chirality is important? vital for proper pharmacokinetics (what body does In an analysis of all single enantiomer drugs to the drug) and pharmacodynamics (what drug launched as a percentage of chiral molecules, does to the body). the ratio increased from 31.6% in 1985-1988 to 4 In fact, mixtures of enantiomers available as 89.8% in 2001-2004 (Fig. 1). It is estimated that racemate drugs are actually fixed-dose combinations sales of unichiral drugs could reach $200 billion in 2 of two different molecules 3 (as regards to their action 2008. A number of factors have contributed to the with binding sites), and pose as much irrationality introduction and popularity of unichiral products since 1980 and more so 1992 onwards. These are: Table 1 : Glossary introduction of enantioselective analytical methods, Chiral: not superimposable on mirror image new synthetic methods for unichiral molecules, Racemate: mixture of two or more enantiomers chromatographic methods for separation and more Enantiomer: Single isomer not superimposable on its mirror importantly US FDA statement in 1992 stating image. Also called ‘unichiral’. that development of racemates would require Eutomer: active isomer justification for inclusion of both the isomers.1, 3 Chirality – Today and Tomorrow’s Way of Treatment 179 Figure 1 : Nature is chiral Table 2 : Differential properties of Rabeprazole enantiomers Dexrabeprazole Levorabeprazole O N O N Na Na Structure N S N S OCH CH CH OCH 2 2 2 3 OCH2CH2CH2OCH3 N CH3 N CH3 Configuration R S Optical rotation Dextro-rotatory Levo-rotatory C-max in 576.106 ± 50.68 234.52 ± 83.40 Our hands and feet are chiral - the right is a mirror image of healthy the left and not superimposable. volunteers (ng/ The fragrance of oranges and lemons is due to S(–) Limonene. ml) 11 R(+) Limonene has a turpentine like odor! AUC0-t in 1972.18 ± 417.63 460.35 ± 227.56 Our bodies can only metabolize (+) glucose and not (–) healthy glucose. volunteers (ng/ ml*hr) 11 (+) leucine tastes sweet while (–) leucine bitter. Half-life 2.74 ± 0.11 1.57 ± 0.89 Figure 2 : Percentage of single enantiomer in healthy drugs against chiral molecules launched from volunteers (hr) 11 4 1985-2004. Isomer to 1.93+0.9 1.04+0.2 racemate ratio Single enantiomer drugs launched as % of chiral molecules of inhibition 100 of ulcers in 90 aspirin-induced 80 ulcers in rat 70 model 12 60 All values are expressed as mean ± standard deviation % 50 40 etc. Although in case of PPIs, the final active 30 moiety is an achiral ‘sulfenamide’, the kinetics of 20 the enantiomer determines the availability of the 10 sulfenamide.5 This chirality of PPIs has led to the 0 1985- 1989- 1993- 1997- 2000- introduction of esomeprazole, S-pantoprazole and 1988 1992 1996 2000 2004 dexrabeprazole. Example of how enantiomers differ In case of rabeprazole, in GERD patients with esophagitis, after 28 days of therapy with An elegant review on the differential properties either the racemate (20 mg) or the R(+) isomer of different enantiomers of commercially available (dexrabeprazole) at half-the racemate dose (i.e. racemates appears in the Journal of Indian Medical 10 mg), there were fewer patients with residual 5 Association. One recent example of dexrabeprazole esophagitis in the dexrabeprazole group is discussed here. The structure of the two enantiomers compared to the racemate. The absolute risk of rabeprazole (usually present in racemate as 1:1 reduction was 27% with a relative improvement mixture) is presented in Table 2. Simply stated, the of 42% and number needed to treat (NNT) of lone pair bond (from the S to the 2 electrons) is only 4. In patients with residual esophagitis, most either looking towards the reader or away, in three patients in the dexrabeprazole group showed dimension. This alters the spatial configuration of signs of healing or improvement compared to the the molecule and hence its interactions with sites rabeprazole group. The absolute risk reduction controlling absorption, distribution, metabolism was 30% with a relative improvement of 46% and 180 Medicine Update 2008 Vol. 18 NNT of only 3. The difference was statistically • Eszopiclone – hypnosis with fewer hangovers significant (p=0.036).6 Some recent unichiral introductions in More examples of differential India properties of enantiomers S-amlodipine : This provides the active CCB Of the two enantiomers in a racemate, one may be component only with longer half-life and consistent inactive, or more active, or having different action, pharmacokinetics due to less inter-subject variability or opposite actions as illustrated below: of S-isomer compared to R-isomer, at half the Only one isomer is active, the other is “inactive”: racemate dose, with less metabolic load. Importantly Levocetirizine (active), Levofloxacin (active), it prevents accumulation of R-amlodipine in elderly, S-amlodipine (active).2 and causes negligible pedal edema. The average incidence of pedal edema observed in the different One isomer is active, the other has “more activity”: SESA trials (n=5165) ranged from 0.75% to 1.93% S-pantoprazole (more potent), Esomeprazole (more with a mean of 1.36%.9 potent).5 Beneficial effects reside in one enantiomer, the S-atenolol : This enantiomer provides the active other enantiomer having antagonistic activity: beta-1 blocker component only, at half the racemate Levo-salbutamol (bronchodilator without pro- dose, and lesser side-effects on switch-over from 8 inflammatory properties).7 racemate to eutomer (active isomer). Beneficial effects reside in one enantiomer, the other S-metoprolol : This provides the beta-1 blocker enantiomer having adverse activity: Esketamine (no component only, at half the racemate dose, hallucination/agitation), Levobupivacaine (no avoiding the beta-2 blocking component, and can cardiotoxicity).2 be administered at high doses without causing beta-2 receptor mediated side effects. It is safer in How single enantiomers may be ‘safer’ poor metabolizers of CYP2D6, and avoids many than racemates drug-drug interactions.7 Chiral purification has introduced many safer S-pantoprazole : This provides the more potent alternatives to existing racemates. Some of the and cytoprotective component of pantoprazole, examples8 are: at half the racemate dose, with consistent • Levocetirizine - a more selective and less pharmacokinetics. It does not accumulate in poor sedative enantiomer metabolizers, and offers lesser potential for drug • S-amlodipine – anti-hypertensive isomer with interactions.5 negligible pedal edema R-ondansetron : This is the clinically more potent • S-metoprolol – anti-hypertensive without beta-2 component, at half the racemate dose. It does not blocking R-isomer prolong QTc interval, hence safer in children and 8 • R-ondansetron – free from QTc prolongation elderly, and offers lesser side-effects. of the racemate / S-isomer Eszopiclone : The S isomer of zopiclone causes • Levosalbutamol- bronchodilator without pro- lesser number of anticholinergic side effects as inflammatory component compared to racemic zopiclone.8 • Levobupivacaine – local anesthetic with lesser Dexibuprofen : Active NSAID enantiomer offering CNS and cardiac toxicity higher gastric safety.10 Chirality – Today and Tomorrow’s Way of Treatment 181 Critical issues in Chirality References Where enantiomers are involved in opposite 1. Joseph Gal. Chiral drugs from a historical point of view. Chirality in Drug Research 2006 WILEY-VCH Verlag GmbH actions as in case of beta-blockers, it is not rationale & Co. KGaA,Weinheim. to allow these “fixed-dose combinations” of 2. Gurjar M. The future lies in chiral purity: A perspective. J enantiomers to continue simply because they have Indian Med Assoc. 2007; 105(4):177-178. 3. FDA’s policy statement for the development of new existed for a long time as racemates e.g. metoprolol. stereoisomeric drugs. http://www.fda.gov/cder/guidance/ When enantiomers exist apparently as “inactive” stereo.htm. Accessed on November 14, 2007 components, the impact of these on the metabolic 4. Murakami H. From Racemates to Single Enantiomers –Chiral Synthetic Drugs over the last 20 Years. Top Curr Chem 2007; system and how they compete with or inhibit the 269: 273–299 action of the metabolizing enzymes need to be 5. Pai V, Pai N. Recent advances in chirally pure proton pump assessed. Proper selection of enantiomers may allow inhibitors. J Indian Med Assoc. 2007; 105: 469-74. matching drugs to poor or extensive metabolizers 6. Pai V, Pai N. Randomized, double-blind, comparative study of dexrabeprazole 10 mg versus rabeprazole 20 mg (e.g. S-metoprolol may be administered to either in the treatment of gastroesophageal reflux disease.
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