Enantiospecific Synthesis and in vitro Activity of Selective Inhibitors of Rat Brain Kynureninase and Kynurenine-3-Hydroxylase

Abstract

Chirality, a phenomenon of dissimetry, is a fundamental characteristic of biological systems. A large amount of endogenous compounds including drug-interacting macromulecules are chiral, thus giving rise to differences in the intermolecular energy involved in the interaction of the chiral drug and the biological target. As a result of such chiral discrimination, drug enantiomers may differ in their pharmacodynamic and pharmacokinetic effects. Due to such differences, particularly in vivo the use of 1:1 mixture of enantiomers (racemates), often fails to display, and occasionally masks the properties of each enantiomer. In searching of selective inhibitors of tryptophane catabolism enzymes, we identified two classes of potent and selective inhibitors represented by 2’-methoxy-benzoylalanine (R,S)-1 and 3’, 4’-dichloro-benzoylalanine (R,S)-2, acting respectively as kynureninase and kynuren- ine 3-hydroxylase selective inhibitors with no activity on the kynurenic acid synthesising enzyme (Kynurenine aminotransferase). Moreover, it is noteworthy that the unsubstituted benzoyl-alanine (R, S)-3, even though endowed with lower potency and selectivity, is by itself an inhibitor of kynurenine-3-hydroxylase.