Drug Chirality And Its Pharmacological Consequences





4.2.1 Nomenclature and designation of stereoisomers 103

4.2.2 The nomenclature problem in generic names 111

4.2.3 Prochirality 112


4.3.1 Terminology used in the pharmacological evaluation of stereoisomers 116

4.3.2 "Purity" of enantiomerically pure drugs 117

4.3.3 Receptor selectivity 119

4.3.4 Quantitative structure—activity relationships 120


4.4.1 Absorption 122

4.4.2 Distribution 124

4.4.3 Metabolism 126

4.4.4 Excretion 133

4.4.5 Pharmacokinetic parameters 134


4.5.1 The pharmacological activity resides in one enantiomer the other being biologically inert 135

4.5.2 Both enantiomers have similar activities 135

4.5.3 Both enantiomers are marketed with different indications 136

4.5.4 The enantiomers have opposite effects 136

4.5.5 One enantiomer may antagonise the side effects of the other 139

4.5.6 The required activity resides in one or both enantiomers but the adverse effects are predominantly associated with one enantiomer 139


4.6.1 Antiarrhythmic agents

4.6.3 Anticoagulants

4.6.4 Antihistamines

4.6.5 Non-steroidal anti-inflammatory drugs

4.6.6 Antimicrobial agents






One in four of all therapeutic agents are marketed and administered to man as mixtures. These agents are not drug combinations in the accepted meaning of the term, i.e. two or more coformulated therapeutic agents, but combinations of isomeric substances the biological activity of which may well reside predominantly in one isomer. The majority of these mixed formulations arise due to the use of racemic mixtures of synthetic chiral drugs and less frequently to mixtures of diastereoisomers. Over the last ten years there has been considerable interest in the area of drug chirality as a result of recent advances in the stereoselective synthesis and stereospecific analysis of chiral molecules. As a result of these advances and the realization of the significance of the pharmacodynamic and pharmacokinetic differences between the enantiomers of chiral drugs there has been increasing concern over the use of racemates, and other stereoisomeric mixtures, in therapeutics. The use of such mixtures may present problems particularly if the adverse effects, or toxicity of the drug is associated with the less active, or inactive isomer, or does not show stereoselectivity. Many authors regard racemates as "compounds which contain 50% impurity" and that their use is "polypharmacy" with the proportions of the materials being dictated by chemical rather than pharmacological or therapeutic criteria. As a result of these concerns drug stereochemistry has become an important consideration for both the pharmaceutical industry and the major drug regulatory authorities.

The extent of the problem can be appreciated from the results of a survey of 1675 drugs carried out in the early 1980s. Of these agents 1200 (72%) were classified as synthetic and 475 (28%) as natural products or semisynthetic agents. Of the compounds classified as natural products or semisynthetics 469 were chiral and of these 461 (98%) were marketed as single isomers. In contrast 29% (480) of the synthetic compounds were chiral with only 3.5% (58) being available as single isomers the remainder (25%) being marketed as racemates. More recent investigations have indicated that the position regarding natural and semisynthetic agents has not changed greatly but that the proportion of synthetic agents available as single isomers had increased. From the above figures it is obvious that drug chirality is an "across-the-board" problem, mixtures of stereoisomers being found in the majority of therapeutic groups.

Biological environments at a molecular level are highly chiral being composed of chiral biopolymers, e.g. proteins, glycolipids and polynucleotides, from the chiral building blocks of L-amino acids and the D-carbohydrates. As nature has made a preference in terms of its stereochemistry it is not surprising that enzymes and receptor systems show a stereochemical preference for one of a pair of stereoisomers. The interaction of a drug with a receptor, or enzyme active site, involves interaction between the functionalities of the drug molecule and complementary sites or groups on the receptor. Such interactions may have considerable steric constraints in terms of interatomic distance and steric bulk between such functionalities. In the case of stereoisomers the three dimensional spatial arrangement of the functionalities is of considerable significance.

Enantioselectivity in drug action should not be surprising as many of the natural ligands are themselves chiral, e.g. neurotransmitters, autocoids, hormones, endogenous opioids etc. Indeed Lehmann has stated that "the stereoselectivity displayed by pharmacological systems constitutes the best evidence that receptors exist and that they incorporate concrete molecular entities as integral components of their active sites".


Stereochemistry is concerned with the three dimensional spatial arrangement of the atoms within a molecule. The prefix stereo originating from the Greek stereos meaning solid or volume. Stereoisomers are compounds which differ only in the three-dimensional arrangement of their constituent atoms in space and such isomers may be divided into two groups namely enantiomers and diastereoisomers. Enantiomers are pairs of compounds which are non-superimposable mirror images of one another and in terms of physicochemical properties, differ only in their ability to rotate the plane of plane polarised light which is equal in magnitude but opposite in direction. Such isomers are said to be chiral (from the Greek chiros meaning handed) and are variously referred to as optical isomers or enantiomorphs (Greek enantios opposite, morph form). The term diastereoisomers refers to all other stereoisomeric compounds regardless of their ability to rotate the plane of plane polarised light and the definition therefore includes both geometrical, i.e. cis/trans isomers and optical isomers. A fundamental distinction between enantiomerism and diastereoisomerism is that in a pair of enantiomers the distances between nonbonded atoms are identical, whereas in diastereoisomers they are not. Thus, the energy content of a pair of enantiomers is essentially identical, whereas a pair of diastereoisomers differ in energy and hence in their physico-chemical properties. This fundamental difference in the properties of the two types of stereoisomer has considerable significance as mixtures of enantiomers cannot be readily separated by standard chemical techniques, whereas diastereoisomers may be separated, in principle at least by distillation, recrystallisation and chromatography.

In terms of the compounds of interest in medicinal chemistry and pharmacology the most frequent cause of chirality arises from the presence of a tetracoordinate carbon atom in a molecule to which four different atoms or groups are attached (4.1), i.e. a chiral or asymmetric centre. The presence of one such centre in a molecule gives rise to a pair of enantiomers, the presence of n such different centres yields 2n stereoisomers and half that number of pairs of enantiomers. Those stereoisomers which are not enantiomeric being diastereoisomeric. Diastereoisomers which differ in configuration about one chiral centre only are termed epimers.

In additional to carbon other atoms frequently found in organic molecules have a coordination number of four and a tetrahedral arrangement of the attached ligands,

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