title: Novel bishydroxamic acids as 5-lipoxygenase inhibitors.
abstract: Two series of novel bishydroxamic acids 2 and 3 (types A and B) were synthesized and tested for inhibition of 5-lipoxygenase from rat basophile leukemia (RBL) cells. Both series were potent inhibitors of the isolated enzyme but only the type B reverse hydroxamic acids possessed significant oral activity. The most potent compound, orally, was 3a, [IC50 = 270 nM; ED50 = 1.86 mg/kg], which compares favorably with the clinically useful 5-lipoxygenase inhibitor, zileuton. Unlike known hydroxamic acid inhibitors, the oral activity in this series appears to be associated with the second hydroxamic acid group. The corresponding monohydroxamic acids retained inhibitor potency, in vitro, with reduced oral activity in a mouse zymosan peritonitis model. Compound 4e [IC50 = 7 nM], a monohydroxamic acid derivative related to 3a, is among the most potent inhibitors of the isolated enzyme yet to be reported.
authors.affiliation: R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869.
authors.forename: K A
authors.initials: KA
authors.lastname: Ohemeng
authors.forename: V N
authors.initials: VN
authors.lastname: Nguyen
authors.forename: C F
authors.initials: CF
authors.lastname: Schwender
authors.forename: M
authors.initials: M
authors.lastname: Singer
authors.forename: M
authors.initials: M
authors.lastname: Steber
authors.forename: J
authors.initials: J
authors.lastname: Ansell
authors.forename: W
authors.initials: W
authors.lastname: Hageman
mesh_terms: D000818:Animals; D015195:Drug Design; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D010538:Peritonitis / Q000517:prevention & control; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000201:enzymology
chemical_list: D006877:Hydroxamic Acids; D016859:Lipoxygenase Inhibitors; D017997:Leukotriene C4; D009637:Masoprocol