4-PHENYL-4-OXO-BUTANOIC ACID-DERIVATIVES INHIBITORS OF KYNURENINE 3-HYDROXYLASE

Kynurenine 3-hydroxylase (KYN 3-OHase) is a key enzyme in the kynureni ne pathway of tryptophan degradation and its inhibition may be an effe ctive mechanism for counteracting neuronal excitotoxic damage. We pres ent here a new class of inhibitors derived from a structure-activity r elationship (SAR) study of the benzoylalanine side-chitin of 1. 2-hydr oxy-4-(3,4-dichlorophenyl)-4-oxo-butanoic acid (8) and 2-benzyl-4-(3,4 -dichlorophenyl)-4-oxo-butanoic acid (10) emerged as the most interest ing derivatives. Enantiospecific synthesis for both enantiomers of 8 a nd diastereomeric salt resolution for those of 10 were successfully ap plied. (C) 1998 Elsevier Science Ltd. All rights reserved.