DIOXALBICYCLOOCTANYL NAPHTHALENENITRILES AS NONREDOX 5-LIPOXYGENASE INHIBITORS - STRUCTURE-ACTIVITY RELATIONSHIP STUDY DIRECTED TOWARD THE IMPROVEMENT OF METABOLIC STABILITY

Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-l ipoxygenase (5-LO) inhibitor, is extensively metabolized at two differ ent 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 tetrahydrop yran ring by a 6,8-dioxabicydo[3.2.1]octanyl moiety, and replacement o f the pendant phenyl ring by a 3-furyl ring, were incorporated in a si ngle molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhib its the oxidation of arachidonic acid to 5-hydroperoxy-eicosatetraenoi c acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B-4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naph thalenenitrile 9ac is accompanied by an improved resistance to oxidati ve metabolism. In addition, 9ac is orally active in the functional mod el of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).