4-Phenyl-4-oxo-butanoic acid derivatives inhibitors of kynurenine 3-hydroxylase

Abstract Kynurenine 3-hydroxylase (KYN 3-OHase) is a key enzyme in the kynurenine pathway of tryptophan degradation and its inhibition may be an effective mechanism for counteracting neuronal excitotoxic damage. We present here a new class of inhibitors derived from a structure-activity relationship (SAR) study of the benzoylalanine side-chain of 1 . 2-hydroxy-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 interesting derivatives. Enantiospecific synthesis for both enantiomers of 8 and diastereomeric salt resolution for those of 10 were successfully applied.