title: Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability.
abstract: Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxy-eicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an improved resistance to oxidative metabolism. In addition, 9ac is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).
authors.affiliation: Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Delorme
authors.forename: Y
authors.initials: Y
authors.lastname: Ducharme
authors.forename: C
authors.initials: C
authors.lastname: Brideau
authors.forename: C C
authors.initials: CC
authors.lastname: Chan
authors.forename: N
authors.initials: N
authors.lastname: Chauret
authors.forename: S
authors.initials: S
authors.lastname: Desmarais
authors.forename: D
authors.initials: D
authors.lastname: Dubé
authors.forename: J P
authors.initials: JP
authors.lastname: Falgueyret
authors.forename: R
authors.initials: R
authors.lastname: Fortin
authors.forename: J
authors.initials: J
authors.lastname: Guay
authors.forename: P
authors.initials: P
authors.lastname: Hamel
authors.forename: T R
authors.initials: TR
authors.lastname: Jones
authors.forename: C
authors.initials: C
authors.lastname: Lépine
authors.forename: C
authors.initials: C
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: McAuliffe
authors.forename: C S
authors.initials: CS
authors.lastname: McFarlane
authors.forename: D A
authors.initials: DA
authors.lastname: Nicoll-Griffith
authors.forename: D
authors.initials: D
authors.lastname: Riendeau
authors.forename: J A
authors.initials: JA
authors.lastname: Yergey
authors.forename: Y
authors.initials: Y
authors.lastname: Girard
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001572:Benzofurans / Q000737:chemistry*; D016084:Bronchoconstriction / Q000187:drug effects; D004355:Drug Stability; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; C093188:L 702539; C101728:L 708780; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D009281:Naphthalenes; D009570:Nitriles; D007975:Leukotriene B4; D016718:Arachidonic Acid; C025348:arachidonic acid 5-hydroperoxide; D001094:Arachidonate 5-Lipoxygenase