title: 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-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.
authors.affiliation: Pharmacia & Upjohn, Chemistry Dept., Nerviano, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Giordani
authors.forename: P
authors.initials: P
authors.lastname: Pevarello
authors.forename: M
authors.initials: M
authors.lastname: Cini
authors.forename: R
authors.initials: R
authors.lastname: Bormetti
authors.forename: F
authors.initials: F
authors.lastname: Greco
authors.forename: S
authors.initials: S
authors.lastname: Toma
authors.forename: C
authors.initials: C
authors.lastname: Speciale
authors.forename: M
authors.initials: M
authors.lastname: Varasi
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D050601:Kynurenine 3-Monooxygenase; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010654:Phenylbutyrates / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism
chemical_list: C116815:2-benzyl-4-(3,4-dichlorophenyl)-4-oxobutanoic acid; C116814:2-hydroxy-4-(3,4-dichlorophenyl)-4-oxobutanoic acid; D004791:Enzyme Inhibitors; D010654:Phenylbutyrates; D014364:Tryptophan; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase