THE RACEMIZATION OF ENANTIOPURE DRUGS - HELPING MEDICINAL CHEMISTS TOAPPROACH THE PROBLEM

In this review, we examine the problem of low configurational stabilit y as encountered for a number of chiral drugs and resulting in racemiz ation or epimerization. The focus is on implications in medicinal chem istry and drug research. When configurational stability is truly low a nd results in half-lives of racemization or epimerization in the order of minutes or hours, the phenomenon has pharmacological significance. When, in contrast, the half-lives of racemization or epimerization ar e in the order of months or years, the phenomenon has pharmaceutical s ignificance and may shorten the shelf-live of the drug. A fast method exists to determine the configurational stability of drug candidates h aving a chiral centre of the type R '' R'RC-H, namely proton-deuterium exchange. The reaction has the considerable advantage that it can be performed with the racemate. In other wards, it allows chiral drug can didates to be screened for configurational stability prior to their re solution. A qualitative estimate of configurational stability is feasi ble, since the substituents around the chiral carbon play a determinin g role in stabilizing or destabilizing the configurational stability o f chiral carbons. In contrast, a quantitative prediction of rates of r acemization appears practically impossible at present in view of the m arked influence of salvation effects. Many examples indicate a mechani sm of general-base catalysis in reactions of isomerization. The pharma cological implication is that racemization or epimerization of chiral compounds in biological media can be expected to be catalyzed by a var iety of endogenous buffers such as plasma proteins, amines, and perhap s thiolates, phosphate and bicarbonate. Thus, it will not be possible to deduce rates of in vivo chiral inversion of drugs from results obta ined in non-biological media. Only experiments conducted in vivo or in biological media such as blood plasma will yield clinically useful fi gures for racemization or epimerization of configurationally labile ch iral drugs.