title: Synthesis and SAR of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and esters and 2-amino-4-aryl-4-oxobut-2-enoic acids and esters: potent inhibitors of kynurenine-3-hydroxylase as potential neuroprotective agents.
abstract: The synthesis and structure-activity relationship of a series of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and esters and 2-amino-4-aryl-4-oxobut-2-enoic acids and esters as potent inhibitors of kynurenine-3-hydroxylase are described. These compounds are the most potent inhibitors of the kynurenine-3-hydroxylase enzyme so far disclosed. Additionally methyl 4-(3-chlorophenyl)-2-hydroxy-4-oxobut-2-enoate (2d), 4-(3-chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid (3d), methyl 4-(3-fluorophenyl)-2-hydroxy-4-oxobut-2-enoate (2f), and 4-(3-fluorophenyl)-2-hydroxy-4-oxobut-2-enoic acid (3f) prevent the increase in the interferon-gamma-induced synthesis of quinolinic acid in primary cultures of cultured human peripheral blood monocyte-derived macrophages.
authors.affiliation: Medicinal Chemistry 3 and Enzyme Medicinal Chemistry 2, Glaxo Wellcome Research and Development, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: S L
authors.initials: SL
authors.lastname: Hind
authors.forename: M
authors.initials: M
authors.lastname: Jansen
authors.forename: J F
authors.initials: JF
authors.lastname: Reinhard
mesh_terms: D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D050601:Kynurenine 3-Monooxygenase; D009682:Magnetic Resonance Spectroscopy; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats
chemical_list: D002087:Butyrates; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D006899:Mixed Function Oxygenases; D050601:Kynurenine 3-Monooxygenase