Chirality in Drug Design and Synthesis

REES

Introduction

This volume records the lectures delivered by a group of distinguished scientists at the 4th Smith Kline and French Research Symposium on Chirality in Drug Design and Synthesis, held in Cambridge in March 1990. They brought together in one forum expertise in the pharmacology, toxicology, mechanism of action and chemical synthesis of chiral drugs and provided a unique opportunity for discussion and debate on these important issues. They thereby amply fulfilled the aim of the Symposium, which was organized with a view to examining firstly the very need for the preparation and study of pure enantiomers of chiral drug substances, secondly the mechanism of interaction of such species with enzymes and receptors, and methods for the study of such interactions and finally, and certainly not least importantly, methods for their synthesis in enantiomerically pure form.

Chiral molecules have intrigued scientists for more than 150 years, and it is interesting in the present context to note that it was a biologist, Pasteur, working before the structural theories of Kekulé, Van’t Hoff and Le Bel had been formulated, who first separated a pair of enantiomers and distinguished among them and their 1:1 mixture or racemate. Interest in the separation of enantiomers from racemic reaction products and in the synthesis of pure enantiomers has continued ever since. However, enantiomerism has always been treated as a rather ‘special’ type of isomerism, probably because ostensibly the only difference between enantiomers is the manner in which they interact with polarized light. One enantiomer has therefore rarely been regarded as an ‘impurity’ when present in a sample of the other enantiomer, in contrast to, say, a mixture of two aromatic positional isomers or a mixture of (E)- and (Z)-alkenes. In fact, this lack of any difference other than optical activity only holds in a truly achiral situation: as soon as any chirality is introduced into the environment of a chiral molecule the enantiomers are differentiated. This will clearly be the case when a chiral drug interacts with an enzyme or receptor, as such biomolecules will typically represent a chiral environment.

The important difference between the way in which chiral and achiral drugs act on a chiral receptor can be effectively illustrated by analogy with a comparison of the game of baseball and the game of golf. Unlike a baseball bat, an achiral object with a variety of symmetry elements, a golf club lacks any element of symmetry and can therefore be made in either right- or left-handed form. A right-handed player (representing the receptor) may thus play to maximum effect only with a right-handed club (representing the drug) and not with a left-handed one. No such distinction arises in the case of the baseball bat (representing an achiral drug). The same is also true of a cricket bat, although it is important to note that in the hands of the player the two edges of the bat become inequivalent and, in use, probe quite different regions of space, the cricket bat being a prochiral object. On the face of it therefore, in the hands of a right-handed player (the receptor), a left-handed club (the ‘wrong’ enantiomer) will be of little more use than, say, a baseball bat representing a ‘normal’ impurity, and the analogy requires that the enantiomer of a drug be treated just as any impurity would. However, a closer acquaintance with the game of golf shows that the situation is not so clear cut. A left-handed one-iron, for example, could be used much more effectively by a right-handed player than could a left handed nine-iron. (Those totally familiar with the game will of course realize that certain putters have a plane of symmetry and are, therefore, prochiral, like the cricket bat.) We might therefore anticipate that drug molecules might behave similarly, with receptors being less enantioselective towards some drugs than to others.

This notion that differences in pharmacological effect of the two enantiomers of a chiral drug must be related to the degree of chirality or perhaps to the degree to which the chiral centre plays a crucial role in the mechanism of action of a particular drug is implicit in Pfeiffer’s rule which equates large differences in pharmacological effect of the enantiomers of a chiral drug with low effective doses. It is important to realize, however, that we have to consider the possibility that our enantiomer may be more than just an ineffective version of its mirror image, and may have dramatically different (and potentially undesirable) pharmacological effects in its own right. Furthermore, processes such as drug absorption, distribution, excretion and metabolism are all potentially subject to enantioselection.

A proper understanding of the complex game of golf clearly requires a thorough understanding of the rules, of the finer points of the way in which it is played and of the structure of the clubs used. By analogy, drug research with chiral molecules requires a clear understanding of the regulatory requirements (the rules) the distribution, mechanism of action and metabolism of drug substances (the game itself) and their synthesis (club manufacture) before a clear cut decision can be made as to whether racemates may be considered acceptable or described as 50% impure. The contributors to this volume demonstrate clearly that the ever-increasing understanding of the mode of action of drug substances reveals a variety of situations with regard to the acceptability of using chiral drugs in racemic or enantiomerically pure form, and that elegant synthetic methodology is available to provide the latter where necessary.

1

Chirality: Pharmacological Action and Drug Development

MARTHA HYNECK, JOHN DENT and JERRY B. HOOK,     Research and Development, Smith Kline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania 19406–2799, USA

Publisher Summary

This chapter discusses that optical activity is caused by molecular asymmetry and that nonsuperimposable mirror-image structures results from this molecular asymmetry. There is a hypothesis that the chiral nature of compounds is because of the fact that carbon constituents can have a non-planar spatial arrangement giving rise to nonsuperimposable mirror images. Most naturally occurring medicinal agents exist in their optically active or single isomer form, such as quinidine and quinine, (-)-morphine, and (+)-digitoxin. However, many synthetic chemicals are produced as the optically inactive racemate. Because of potential pharmacological, pharmacokinetic, and toxicological issues, some scientists suggest that only single isomers should be considered for drug development and regulatory approval. Pharmacokinetic investigations into the disposition of enantiomers have enhanced the understanding of racemic drug action and have helped to understand previously inexplicable pharmacodynamic outcomes following administration of racemates to patients.

Introduction

The field of stereochemistry has been developing since the early 1800s when Jean-Baptiste Biot, a French physicist, discovered optical activity in 1815. By the middle of the 19th century, Louis Pasteur had performed the first resolution of a racemic mixture, d- and l-tartaric acid. From this work Pasteur made the remarkable proposal that optical activity was caused by molecular asymmetry and that nonsuperimposable mirror-image structures resulted from this molecular asymmetry. Despite considerable scepticism within the community of chemists, scientists from several countries continued exploring this new field and with each new scientific contribution the relationship between optical activity and molecular asymmetry unfolded. By the end of the 18th century, Van’t Hoff of Holland and Le Bel of France strengthened Pasteur’s proposal by hypothesizing that the chiral nature of compounds was due to the fact that carbon constituents could have a non-planar spatial arrangement giving rise to nonsuperimposable mirror images (Drayer, 1988a).

Today we realize that most naturally occurring medicinal agents exist in their optically active or single isomer form, such as quinidine and quinine (Fig. 1), (–)-morphine and (+)-digitoxin. However, many synthetic chemicals are produced as the optically inactive racemate. According to a survey reported in 1984, nearly 400 racemates were prescribed for patients in the 1970s and 1980s (Mason, 1984). The fact that so many drugs are administered as racemic mixtures has led to considerable concern and debate (Ariens, 1984; Caldwell et al., 1988). Because of potential pharmacological, pharmacokinetic and toxicological issues, some scientists suggest that only single isomers should be considered for drug development and regulatory approval. In support of racemic drug development, proponents cite examples of racemic compounds that have been administered for years without untoward effects, and the technical difficulties associated with large-scale production of single isomers.

Fig. 1 Structure of quinidine and quinine.

In the past few decades pharmacological and toxicological investigations have clearly demonstrated significant differences in the biological activity of some isomeric pairs. Recently, pharmacokinetic investigations into the disposition of enantiomers have enhanced our understanding of racemic drug action and have helped us to understand previously inexplicable pharmacodynamic outcomes following administration of racemates to patients.

2 Terminology

A myriad of terms in stereochemistry are used to define molecules and to describe the relationship between molecules and receptors in the body (Wainer and Marcotte, 1988; Caldwell et al., 1988). This section is not meant to be an exhaustive review of the field, but to cover the major terms and concepts to be used.

Isomers are unique molecular entities composed of the same chemical constituents with common structural characteristics. Stereoisomers are those isomers whose atoms, or groups of atoms, differ with regard to spatial arrangement of the ligands. Stereoisomers can be either geometric or optical isomers. Geometric isomers are stereoisomers without optically active centres; for these compounds terminology such as cis or Z isomer (meaning together or same side), and trans or E isomer (meaning opposite side) are used to describe the spatial arrangement.

Optical isomers are a subset of stereoisomers, from which at least two isomers are optically active; these compounds are said to possess chiral or asymmetrical centres. The most common chiral centre is carbon, but phosphorus, sulphur and nitrogen can also form chiral centres. If the isomer and its mirror image are not superimposable, the pair are referred to as enantiomers or optical antipodes. A mixture of equal portions (50/50) of each enantiomer is called a racemate. Optical isomers that are not enantiomers are called diastereoisomers or diastereomers. One type of diastereomer is a molecule with two chiral centres; all four isomers of this diastereomer are not superimposable mirror images of each other. Whereas enantiomers have physically identical characteristics such as lipid solubility and melting/ boiling points, diastereomers can have different chemical and physical characteristics.

The earliest method of differentiating one enantiomer from its antipode was to assign the d or (+) designation to stereoisomers which caused a clockwise rotation of a beam of polarized light, and l or (–) to stereoisomers which cause a counterclockwise rotation of the polarized light. Since this system did not describe the actual spatial arrangement, the Fischer convention was developed (Wichelhaus et al., 1919; Freudenberg, 1966). In this system, the molecule had to be converted to a compound of known configuration, such as (+)-glyceraldehyde and then named accordingly. Due to the difficulty of the chemical transformation, the awkwardness of the convention in some situations (i.e. diastereomers) and the confusion between small and capital letter system (d and d), the convention has fallen into disfavour.

The Cahn–Ingold–Prelog convention is currently recommended for specifying the configuration of the isomers (Cahn et al., 1966). In this method, the ligands around the chiral centre are ‘sized’ according to their atomic number (Fig. 2). The molecule is then positioned with the smallest ligand(s) away from the viewer (‘into the page’). If the sequence of the remaining three ligands are arranged so that the largest (L) to the smallest (S) size is in a clockwise manner, the molecule is assigned the R or rectus; the counterclockwise sequencing is given the S or sinister designation.

Fig. 2 The Cahn–Ingold-Prelog convention. Reprinted from Wainer and Marcotte (1988) by courtesy of Marcel Dekker Inc.

Two other terms may be used to compare the pharmacological activity of two enantiomers. It has been proposed that the isomer imparting the desired activity be called the eutomer and that the ‘inactive’ or unwanted isomer be labelled the distomer (Lehmann, 1986). From this comes the eudismic ratio which is the ratio of the potencies for the two enantiomers. These eudismic ratios can be used to describe in vitro or in vivo potency ratios, and there could potentially be more than one eudismic ratio for a racemate if the compound had more than one pharmacological