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See Attached REVIEWS PUTTING CHIRALITY TO WORK: THE STRATEGY OF CHIRAL SWITCHES Israel Agranat*‡, Hava Caner‡ and John Caldwell* Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from ‘chiral switches’ of established racemates. Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a ‘line extension’ of a major racemic drug with patents that are expiring. “And should not I spare Nineveh, that great city, wherin Emergence of chirality in drug development CHIRALITY The geometric property of a are more than sixscore thousand persons that cannot One of the main features of the living world is its rigid object (or spatial discern between their right hand and their left hand; chirality14,16,17 (FIG. 2). CHIRAL CENTRES are common in the arrangement of points or atoms) and also much cattle”. amino-acid and carbohydrate building blocks of proteins, of being non-superimposable carbohydrates and nucleic acids. These biomolecules are on its mirror image; such an Book of Jonah, Chapter 4,Verse 11 object has no symmetry made up of units that have the same sense of chirality — elements of the second kind The issue of drug CHIRALITY is now a major theme in the the 21 essential amino acids are all L-enantiomers, σ (a mirror plane, = S1;a centre design, discovery and development of new drugs, whereas most carbohydrates have the D-CONFIGURATION. of inversion, i = S ;or a 2 underpinned by a new understanding of the role of Essential physiological processes are, therefore, homo- rotation–reflection axis, S ). 2n molecular recognition in many pharmacologically chiral — they show 100% STEREOSELECTIVITY and only If an object is superposable on 1–7 its mirror image, it is described relevant events . There are two principal scenarios in involve one of all the possible stereoisomers of key as being achiral. chiral drug development: the de novo development of molecules18. When exogenous compounds are introduced an enantiomerically pure drug, or a switch from an into the body, physiological processes show a high degree existing racemic drug to one of its isomers in a pure of chiral distinction (a term that is preferred to chiral dis- form8. Single-enantiomer drugs are a rapidly growing crimination)19, with the effects of different stereoisomers proportion of new drugs that are introduced to the often being markedly different as a consequence of their market, rising from ~20% of new drugs ten years ago differential interaction with chiral targets, such as recep- to almost 75% today. Today,‘chiral switches’9–13, which tors, enzymes and ion channels. exploit single enantiomers of existing RACEMATES After decades of essentially two-dimensional pharma- (racemic mixtures), are an important feature of drug cology and therapeutics, in which the pharmacopoeia *Division of Biomedical development portfolios. Although they have limited was dominated by racemates, the early 1980s saw a re- Sciences, Imperial College application in the generic marketplace, they are discovery of stereochemistry5. This was driven by the Faculty of Medicine, increasingly being used to allow ‘line extensions’ of emergence of new technologies that allowed the prepara- Sir Alexander Fleming blockbuster drugs — for example, omeprazole.There tion of pure enantiomers in quantity, leading to a renewal Building, London SW7 2AZ, 7 United Kingdom. are now several examples of well-timed switches of of interest in the stereochemistry of drug action . In par- ‡Department of Organic racemic drugs that have PATENTS that are about to expire allel, advances in stereoselective bioanalysis led to a new Chemistry, The Hebrew — rapid and economical ‘bridging’ strategies have been awareness of the importance of stereoselective pharma- University of Jerusalem, devised to allow efficient development and speedy regu- cokinetics and drug disposition7. It was realized that Jerusalem 91904, Israel. latory approval of switched single enantiomers (see FIG. 1 most drugs were actually mixtures of stereoisomers, Correspondence to I.A. e-mail: [email protected] and the definitions in the margins for the basic termi- which were divided by Ariëns into the eutomer — in doi:10.1038/nrd915 nology of stereochemistry14,15). which the desired effects are concentrated — and the NATURE REVIEWS | DRUG DISCOVERY VOLUME 1 | OCTOBER 2002 | 753 © 2002 Nature Publishing Group REVIEWS Isomer One of several chemical species (or molecular entities) that have the same stoichiometric molecular formula but different constitutional formulae or different stereochemical formulae, and hence potentially different physical and/or chemical properties. CONFORMATION Constitutional Isomers Stereoisomers The spatial arrangement of the Isomers that differ in constitution and are described Isomers that have identical constitution, but which differ in the atoms affording distinction by different line formulae. arrangement of their atoms in space. between stereoisomers, which can be interconverted by rotations about formally single bonds. A conformer is one of a set of stereoisomers, each of Diastereomers which is characterized by a Enantiomer Stereoisomers that are not related as mirror images. conformation that corresponds One of a pair of molecular entities, which are mirror Diastereoisomers are characterized by differences in physical images of each other and are non-superimposable. properties, and by some differences in chemical behaviour to a distinct potential energy towards achiral, as well as chiral, reagents. minimum. Figure 1 | Basic terminology of stereochemistry. CONFIGURATION In the context of stereochemistry, the term is restricted to the arrangements distomer, which is at best an inactive ‘isomeric ballast’ As these scenarios emerged, it became clear that the of atoms of a molecular entity and at worst, the molecule in which toxicity is concen- failure to address issues raised by the stereochemistry in space that distinguishes trated20. The experience of the past 15 years has allowed of racemic drugs was the cause of some drug–drug stereoisomers, the isomerism between which is not due to us to move from this rather simplistic distinction to an interactions, severe adverse reactions and withdrawals conformational differences. appreciation of the differentiation of the relative contri- from the market. It further became evident that the use The absolute configuration is the butions of stereoisomers to overalldrug action1,5,21. of stereochemically pure drugs should be advanta- spatial arrangement of the atoms If one enantiomer is responsible for the activity of geous, as they would be expected to reduce the total of a chiral molecular entity (or group) and its stereochemical interest, its paired enantiomer could be inactive, have dose given, simplify the dose–response relationship, description — for example, R or some activity of interest, be an antagonist of the active remove a source of intersubject variability and mini- S (for chiral centres) and M or P enantiomer, have a separate activity of interest or have a mize toxicity due to the inactive stereoisomer5. These (for chiral axes). separate and undesirable activity1,5,22. pharmacodynamic and pharmacokinetic factors led to an increasing preference for single enantiomers in both RACEMATE An equimolar mixture of a pair industrial and regulatory circles. The data in FIG. 3 of enantiomers. It does not have show a clear trend towards single-enantiomer new optical activity. The chemical chemical entities (NCEs), both in development and in name or formula of a racemate is those compounds reaching regulatory approval, which distinguished from those of the enantiomers by the prefix (±)- began in the late 1980s, when a marked preference for 23 or rac- (or racem-), or by the defined stereoisomers of new drugs was established . symbols RS and SR. Worldwide sales of chiral drugs in single-enantiomer forms continued to grow at an annual rate of >13% in PATENT 2000 to US $133 billion, and by 16.7% in 2001 to US A grant by the state of exclusive rights for a limited time (in most $147.2 billion. 40% and 36% of all drug sales in 2000 jurisdictions 20 years from filing and 2001, respectively, were of single enantiomers, date) in respect of a new and compared with 33% in 1999 (REF. 11). The debate about useful invention. The patentable the relative merits of racemates and single enantiomers invention must be new, it must involve an inventive step and it was short lasting, and it was resolved emphatically in 5,21 must be capable of industrial favour of the latter . An analysis of the new molecu- application. lar entities (NMEs) that were approved by the US Food and Drug Administration (FDA) in 1998–2001 CHIRAL CENTRE gave the following approximate distribution: 52% (Chirality centre). An atom that holds a set of ligands in a spatial achirals; 30% single enantiomers with several chiral arrangement, which is not centres; 7% single enantiomers with one chiral centre; superimposable on its mirror 7% racemates; and 4% multiple diastereomers24 (see image. A chiral centre is, Center for Drug Evaluation and Research (CDER) therefore, a generalized extension of the concept of the website). This distribution indicated that there is a sig- asymmetric carbon atom to nificant proportion of racemates among recently central atoms of any element. approved NMEs. A
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