title: Studies on 5-lipoxygenase inhibitors. I. Synthesis and 5-lipoxygenase-inhibitory activity of novel hydroxamic acid derivatives.
abstract: A series of novel hydroxamates has been prepared and tested for inhibitory activity towards rat polymorphonuclear leukocyte (PMN) 5-lipoxygenase (5-LO) in vitro and towards neutrophil migration in the rat air pouch model of inflammation in vivo. Many 3,4-dihydronaphthyl compounds were potent inhibitors of 5-LO, and several compounds were potent inhibitors of neutrophil migration. The most potent 3,4-dihydronaphthyl compound, N-[[(3,4-dihydro-5-phenoxy)-2-naphthyl]methyl]-N-hydroxy-N'-ethylurea (FR122788, 18) had an IC50 of 25 nM in the 5-LO assay, and strongly reduced neutrophil migration in the rat air pouch model at 1 mg/kg (p.o.). FR122788 also had an ameliorating effect in a rat hepatitis model induced by D-galactosamine, with an ED50 values of 14.6 mg/kg (p.o.) for glutamate oxaloacetate transaminase (GOT) and 16.8 mg/kg (p.o.) for glutamate pyruvate transaminase (GPT).
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yatabe
authors.forename: Y
authors.initials: Y
authors.lastname: Kawai
authors.forename: T
authors.initials: T
authors.lastname: Oku
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D005688:Galactosamine; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis*; D007249:Inflammation / Q000188:drug therapy; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C113401:FR 122788; D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D005688:Galactosamine; D014508:Urea; D019061:src-Family Kinases