title: Leukotriene biosynthesis inhibition by aryl and aroyl substituted naphthoquinones.
abstract: Naphthoquinones are known to inhibit 5-lipoxygenase. In particular, CGS 8515 (methyl 2-[(3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino]benzoate) has been studied in detail. However this potent and selective 5-lipoxygenase inhibitor has a short duration of action and poor bioavailability. To improve the duration of action we have prepared a series of carbon substituted naphthoquinones. Several members of this series have demonstrated potent in vitro inhibition of 5-LO (IC50's less than 10(-6) M) and at doses of 1 mg/kg iv completely inhibited LTB4 production measured in ex vivo A23187-stimulated blood from dogs. The duration of action measured by the ex vivo assay was improved up to threefold over CGS 8515.
authors.affiliation: Research Department, CIBA-GEIGY Corp., Summit, NJ 07901.
authors.forename: D M
authors.initials: DM
authors.lastname: Roland
authors.forename: W M
authors.initials: WM
authors.lastname: Macchia
authors.forename: K S
authors.initials: KS
authors.lastname: Grim
authors.forename: E F
authors.initials: EF
authors.lastname: Kimble
authors.forename: D H
authors.initials: DH
authors.lastname: White
authors.forename: T J
authors.initials: TJ
authors.lastname: Kowalski
mesh_terms: D000818:Animals; D001682:Biological Availability; D000001:Calcimycin / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006207:Half-Life; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D011863:Radioimmunoassay; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D062367:ortho-Aminobenzoates; C055523:methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate; D007975:Leukotriene B4; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine