Practitioners' Section

427 428 SAFER MOLECULES THROUGH CHIRALITY PRACTITIONERS’ SECTION development of safer alternatives to existing racemates. DEVELOPMENT OF SAFER MOLECULES THROUGH CHIRALITY Basics of chirality[1-4] Compounds can be chiral or achiral (non-chiral). P. A. PATIL*, M. A. KOTHEKAR** Chiral compounds possess the property of handedness, i.e., they may be right-handed or Figure 1: Chiral structure of ibuprofen ABSTRACT left-handed. These two - left- and right-handed nomenclature are mutually exclusive. R - forms of a chiral compound are identical in Many of the drugs currently used in medical practice are mixtures of enantiomers enantiomer of one compound may be their structural formulas but differ in spatial (racemates). Many a times, the two enantiomers differ in their pharmacokinetic and dextrorotatory, while another compound may arrangement so that one form is exactly a mirror pharmacodynamic properties. Replacing existing racemates with single isomers has have its S enantiomer as dextrorotatory. resulted in improved safety and/or efficacy profile of various racemates. In this review, image of the other but the two forms are not superimposable on one another. This is akin to pharmacokinetic and pharmacodynamic implications of chirality are discussed in brief, A collection containing only one enantiomeric pair of gloves, socks or hands. An achiral followed by an overview of some important chiral switches that have yielded safer form of a chiral molecule is called an optically alternatives. These include levosalbutamol, S-ketamine, levobupivacaine, S-zopiclone, object exists only in one form and there is no pure, chirally pure or enantiomerically pure levocetirizine, S-amlodipine, S-atenolol, S-metoprolol, S-omeprazole, S-pantoprazole possibility of left- or right-handedness. This compound, while collection of equal amounts and R-ondansetron. Few potential chiral switches under evaluation and some chiral existence of left- or right-handedness of a of the two enantiomeric forms is called a switches that have not been successful are also discussed. compound is referred to as chirality. Chirality racemate [Figure 2]. or asymmetry can arise in several ways in a Key words: Chiral switch, enantiomer, racemate, safety molecule but most commonly it is due to the Pharmacokinetic and pharmacodynamic presence of an asymmetric carbon (most implications of chirality common), nitrogen or sulfur in the molecule. An Alternatives to existing molecules are promising efficacy. From time to time, All the pharmacokinetic processes, viz, asymmetric carbon atom is one to which four developed with the ultimate objective of structural changes in existing drugs had absorption, distribution, metabolism and different atoms or groups (ligands) are attached. increasing efficacy and/or enhancing safety, opened up safer alternatives. One of the excretion may be influenced by chirality. This carbon atom exists in two different spatial in view of limitations of modern therapeutic currently adapted modalities to enhance Active transport processes may discriminate orientations in a manner that ligands in one agents. The quest for enhancing the efficacy safety and/or efficacy of existing agents is between the enantiomers, with implications on orientation are not superimposable on ligands and safety profile of modern therapeutic the ‘Chiral Switch.’ Switching from existing bioavailability - e.g., esomeprazole is more of the other. Asymmetric carbon thus imparts agents has made the medical fraternity racemate to one of its isomers has provided bioavailable than racemic omeprazole.[5] The left- or right-handedness to the molecule. witness an array of generations of drugs in safer alternatives to drugs ranging from volume of distribution of levocetirizine has Figure 1 depicts chiral structure of ibuprofen. almost all therapeutic areas. Drugs like antihistaminics like cetirizine to anesthetics been shown to be significantly smaller than thalidomide, cisapride, terfenadine had fallen like ketamine. The increasing availability of that of its dextro enantiomer, which is a Each form (left- or right-handed) of a chiral back due to safety concerns despite their single-enantiomer drugs promises to provide positive aspect in terms of both safety and clinicians with safer, better-tolerated and more compound is called an ‘enantiomer’ or an *Professor and Head, Dept. of Pharmacology, J. N. ‘isomer.’ The enantiomers are denoted as R Medical College, Belgaum - 590 010, Karnataka, efficacious medications for treating patients. **Manager Medical Services, Emcure It is incumbent upon the medical fraternity to or S according to ‘absolute descriptor’ Pharmaceuticals Ltd., 255/2, Rajiv Gandhi IT Park, convention proposed by Cahn, Prelog and Phase I, MIDC Hinjwadi, Pune - 57, India be familiar with the newly introduced chiral switches and their rationale. This review Ingold or they are denoted as dextro (+) or Correspondence levo (-) depending on clockwise or Mudgal Anantrao Kothekar, Manager Medical Services, discusses basics of chirality, its Emcure Pharmaceuticals Ltd., 255/2, Rajiv Gandhi IT Park, pharmacokinetic and pharmacodynamic anticlockwise rotation of plane-polarized light Phase I, MIDC, Hinjwadi, Pune - 57, India. Figure 2: An optically pure compound and a racemate E-mail: [email protected] implications and how chirality is used for by them respectively. The two systems of Indian J Med Sci, Vol. 60, No. 10, October 2006 Indian J Med Sci, Vol. 60, No. 10, October 2006 INDIAN JOURNAL OF MEDICAL SCIENCES 429 430 SAFER MOLECULES THROUGH CHIRALITY efficacy.[6] Drug metabolizing enzyme systems S-amlodipine.[11] The single active Pharmacokinetic differences result in ketamine is eliminated more rapidly as a are also subject to stereoselective influences. enantiomers hold promise only if it is proved different spectra of interactions for the two single enantiomer than as a component of Two isomers of a drug are often metabolized that they don’t undergo chiral inversion to a isomers. Pharmacokinetic differences may the racemate since R-ketamine inhibits the at different rates. This may result in significant extent. also result in one isomer being retained more elimination of S-ketamine.[19] Thus the accumulation of the inactive enantiomer or in poor metabolizers than its counterpart. recovery time after S-ketamine is shorter than rapid elimination of the active one and vice Pharmacodynamic implications of chirality Activity at undesired targets is a that after the racemate, which is a favorable versa. Two isomers of a drug also induce or could be easily understood with the example pharmacodynamic mechanism of adverse property for an anesthetic agent. In clinical inhibit the cytochrome enzymes of a drug-receptor model as depicted in effects due to the distomer. The idea of studies, use of S-ketamine was associated stereoselectively. Figure 3. As the two isomers of a drug have investigating single stereoisomers following with a remarkably smoother emergence different spatial configurations, their the observation of unacceptable adverse period, a profound postoperative analgesia The phenomenon of ‘Chiral Inversion’ adds to complementary binding sites are also effects with the racemate is not new. D- and a more rapid recovery of cerebral the complexity. Chiral inversion is conversion expected to be different. One isomer may penicillamine, dextromethorphan and functions. The incidence of psychotomimetic of one enantiomer into its mirror image. For bind precisely to the target sites (receptor, levodopa are well-known examples where the phenomena was negligibly less after S example, the S form of ibuprofen is active enzyme, etc.), while the other may have an other isomer is associated with adverse ketamine in comparison to racemic but significant R (inactive enantiomer) to S imprecise binding. This inactive isomer effects and hence not used. Following are ketamine.[20] inversion takes place in the body.[7] Therefore, (commonly referred to as ‘distomer’) may bind some recent examples where single isomers a certain amount of S-ibuprofen is precisely to other sites that are not the have enhanced safety profile over the Levobupivacaine: The active bupivacaine theoretically expected to be less effective intended targets. In this way, whenever a drug racemate. with less CNS and cardiac toxicity than the racemate containing similar amount exists as a racemate, the one isomer may Bupivacaine has been the most widely used of S-ibuprofen. Clinical studies have however be active while the other isomer may have: Levosalbutamol: Salbutamol salvaged local anesthetic for years. In vitro animal shown a superior efficacy and enhanced 1. No activity. from its antagonist studies show that levobupivacaine has less safety with S-enantiomer as compared to that 2. Some activity. The bronchodilator activity of racemic cardiotoxic effects and less toxic effects on of the racemate containing similar amount of 3. Antagonistic activity. salbutamol resides in its levorotatory R the CNS in comparison with both S-ibuprofen.[8] Harmful intermediates are 4. A completely separate beneficial activity. enantiomer and the dextrorotatory S dextrobupivacaine and bupivacaine itself.[21] released during R-to-S conversion upon 5. A completely separate adverse activity. enantiomer has been found to be virtually Studies in human volunteers confirmed these administration of racemate, whereas inactive at therapeutic concentrations.[12] To results. Equal potency of levo- and racemic administration of S-ibuprofen results in no

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