Dioxabicyclooctanyl Naphthalenenitriles as Nonredox 5-Lipoxygenase Inhibitors: Structure−Activity Relationship Study Directed toward the Improvement of Metabolic Stability

Citations Over Time

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).

Related Papers

• → Inhibition of platelet arachidonic acid 12-lipoxygenase by acetylenic acid compounds(1981)69 cited
• → Enzymatic Production of 15-Hydroxyeicosatetraenoic Acid from Arachidonic Acid by Using Soybean Lipoxygenase(2014)13 cited
• → Relative conversion of arachidonic acid through lipoxygenase and cyclooxygenase pathways by homogenates of diseased periodontal tissues(1983)37 cited
• → Generation of lipoxygenase products in the avascular tissues of the eye(1985)20 cited
• → Lipoxygenase Metabolites(1988)