Chirality and nonsteroidal anti-inflammatory drugs

The nonsteroidal anti-inflammatory drugs (NSAIDs) are of significant clinical importance and include congeners of many chemical classes, some of which incorporate an asymmetric or chiral carbon atom. With very few exceptions, chiral NSAIDs have bi:en marketed for clinical use as racemates. However, it is apparent that differences, sometimes major, exist between enantiomers in terms of their pharmacological and toxicological properties. With regard to the ability of chiral NSAIDs to inhibit cyclo-oxygenase, their chief mechanism of action, major or exclusive activity is confined to enantiomers of the S-stereoconfiguration. Accordingly, it is questionable whether the R-antipodes should be included in the final drug product for use in the clinic. In addition to differences between enantiomers in terms of their pharmacodynamic properties, pharmacokinetic differences are possible for chiral NSAID isomers, and these may modulate preexisting enantioselectivities at the site of action of such compounds. As a consequence. a considerably simpler pharmacological profile is likely to result from the use of single enantiomers versus racemic mixtures.