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

Bioorg Med Chem Lett. 1998 Oct 20;8(20):2907-12. doi: 10.1016/s0960-894x(98)00517-4.

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-oxobutanoic 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.

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / enzymology
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Kynurenine 3-Monooxygenase
  • Liver / drug effects
  • Liver / enzymology
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Phenylbutyrates / chemistry*
  • Phenylbutyrates / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Tryptophan / metabolism

Substances

  • 2-benzyl-4-(3,4-dichlorophenyl)-4-oxobutanoic acid
  • 2-hydroxy-4-(3,4-dichlorophenyl)-4-oxobutanoic acid
  • Enzyme Inhibitors
  • Phenylbutyrates
  • Tryptophan
  • Mixed Function Oxygenases
  • Kynurenine 3-Monooxygenase