Academic Supplement The Development of Si n g l e - I s o m e r M o l e c u l e s : Why and How By Andrew J. Hutt, PhD ABSTRACT to know that their physician had just prescribed them two, Until relatively recently the three-dimensional nature of or possibly four, “drugs” rather than one. It may well sur- d r ug molecules has been largely neglected, with appro x i- prise them even more to find that their physician was mately 25% of marketed drugs being mixtures of agents u n a w a re of that fact and had not done so as a conscious rather than single chemical entities. These mixtures are not act for their therapeutic benefit. combinations of drugs but mixtures of stereoisomers, gener- These mixtures of “drugs” arise as a result of the use of ally racemates of synthetic chiral drugs. The individual racemates (an equal-parts mixture of a pair of enan- enantiomers present in such mixtures frequently differ in both tiomers), and other combinations of stereoisomers, rather their pharmacodynamic and pharmacokinetic profiles as a than single chemical entities of chiral drug molecules. result of stereochemical discrimination on interaction with The individual components of these mixtures fre q u e n t l y chiral biological macromolecules (enzymes and re c e p t o r s ) . d i ffe r in terms of their pharmacodynamic and pharm a c o- The use of such mixtures may present problems if their kinetic profiles and their use may present problems if adverse effects are associated with the less active stere o i s o m e r their adverse effects are either associated with the “inac- or do not show stere o s e l e c t i v i t y. In addition, interactions tive” isomer or do not show stereoselectivity. between enantiomers may occur such that the observed activ- In recent years, as a result of advances in methodology ity of the racemate is not simply the product of the effects of associated with stereoselective synthesis and stere o s p e - the individual enantiomers. Since the mid-1980s there has cific analysis of chiral drug molecules, together with the been an ongoing “racemate-versus-enantiomer” debate with i n c reasing realization of the potential significance of the the potential advantages of single-isomer products, including d i ff e r ential biological pro p e rties of stereoisomers, dru g i m p roved selectivity of action and potential increase in thera- s t e re o c h e m i s t r y has become a topical subject. The issue peutic index, being highlighted. As a result, re g u l a t o r y of stereochemistry has been examined in both the popular authorities have issued guidelines for dealing with chiral lay and scientific pre s s 2 - 7 with headlines such as: “Dru g molecules, and the number of single enantiomer agents pre- f i r ms sort their lefts from their rights.”5 In practically all sented for evaluation has increased. Racemic mixtures may such articles, the issue of drug stere o c h e m i s t r y is still be developed but re q u i re justification such that the risk- a d d ressed in fairly emotive terms, citing the example of benefit ratio may be assessed. In addition to new chemical the teratogen thalidomide (see below) as an instance entities, a number of “old” mixtures are being re-examined as w h e r e the use of a single stereoisomer would have pre- potential single-isomer products, the chiral switches, with vented the tragedy of the early 1960s. the potential for an improved therapeutic profile and possi- The magnitude of the stere o c h e m i s t ry problem in ther- bly new indications. However, for the majority of agents apeutics may be appreciated from a survey carried out in c u r rently marketed as mixtures, relatively little is known the 1980s of 1,675 dru g s . 8 Of these agents, 1,200 were c o n c e rning the pharmacological or toxicological pro p e rt i e s classified as synthetic, of which 480 were chiral with 58 of the individual enantiomers. being marketed as single stereoisomers (ie, approximately C N S S p e c t ru m s . 2002:7(suppl 1):14-22 25% of the agents examined were used as mixtures of s t e reoisomers). From these figures, it is obvious that dru g INTRODUCTION s t e r e o c h e m i s t r y is not associated with, or restricted to, p a rticular therapeutic groups of drugs but is an acro s s - “...the sad truth is that we still learn most of our chemistry the-board problem. in Flatland, to the detriment of our science.” – Sir John Cornforth (1981)1 The lack of knowledge of drug stere o c h e m i s t ry amongst physicians is probably not surprising for two main re a s o n s : Until relatively re c e n t l y, pharmacology has been a (1) the lack of readily available information concerning dru g Flatland science, the three-dimensional nature of dru g s t e r e o c h e m i s t r y in the sources that physicians utilize, molecules being largely neglected. In terms of therapeu- together with the associated complexity of stere o c h e m i c a l tics, the majority of patients would probably be surprised t e rminology; and (2) a physician could reasonably expect D r. Hutt is lecturer in pharmaceutical chemistry in the Department of Pharm a c y, King’s College London, in London, England. D i s c l o s u re : This work was funded by Forest Pharmaceuticals, Inc. M e d Works Media 14 April 2002 Academic Supplement the pharmaceutical industry, together with the re g u l a t o ry a result of their helical stru c t u res (ie, the α-helix of pro t e i n s agencies, to provide them with the most appropriate mate- and the double helix of DNA) in the same way that a spiral rial available irrespective of stereochemical considerations. s t a i r case or corkscrew may have either a right- or left- H o w e v e r, with the advent of the so-called r a c e m i c or c h i r a l handed turn. In the case of the above examples both helices s w i t c h (see below), and the possibility that both single a r e right-handed. The stereochemical homogeneity of s t e reoisomer and racemic mixture preparations of a dru g n a t u r e was acquired very early in evolutionary time may be available at the same time, it is essential that the s c a l e s , 1 3 , 1 4 and as nature has made a pre f e rence in terms of p rescriber is aware of the nature of the material being used its stere o c h e m i s t ry it should not be surprising that enzymes ( m i x t u re or single compound) and to have an appreciation of and receptor systems almost always show a stere o c h e m i c a l the drug stere o c h e m i s t ry issue. p re f e rence for one or the other of a pair of enantiomers, and The fundamental aspects of stere o c h e m i s t ry, together that many of the natural ligands for these systems (eg, neu- with the associated terminology and nomenclature, have rotransmitters, hormones, endogenous opioids, etc.) are been addressed by Dr. Gal (pages 8-13). This article will themselves single isomer chiral molecules. attempt to explain where and how discrimination between The diff e rential biological “activity” of stereoisomers is s t e reoisomers occurs in biological systems, together with the not a new phenomenon in spite of the considerable intere s t possible consequences of such discrimination and the cur- over the last two decades. In 1858, Pasteur showed that the rent re g u l a t o ry position with respect to chiral compounds. mould Penicillium glaucum metabolized (+)-tartrate more rapidly than the (-)-enantiomer. This was followed in 1886 BIOLOGICAL DISCRIMINATION by Piutti’s observation that the (+)-enantiomer of OF STEREOISOMERS asparagine had a sweet taste whereas (-)-asparagine was Enantiomers are pairs of stereoisomers that are related as i n s i p i d . 1 5 The diff e r ential pharmacodynamic activity of non-superimposable mirror images, and other than their d rug enantiomers was initially re p o rted in the early years of e ffect on the rotation of the plane of plane-polarized light, the last century by the British pharmacologist Cushny,1 6 have identical physicochemical pro p e rties (Figures 1 and who demonstrated diff e r ences in the activity of atro p i n e 2 ) . 9-12 As a result, diff e r ences between enantiomers are , and (-)-hyoscyamine and (-)- and (+)-adrenaline; Cushny under normal circumstances, difficult to detect. However, when placed in a “chiral environment” these diff e re n c e s become more marked.