title: Substituted arylmethyl phenyl ethers. 1. A novel series of 5-lipoxygenase inhibitors and leukotriene antagonists.
abstract: A series of new substituted arylmethyl phenyl ethers has been prepared. These compounds were tested as inhibitors of 5-lipoxygenase (5-LO) in rat neutrophils, in vitro antagonists of leukotriene-induced contraction of guinea pig (GP) lung parenchymal strips, and inhibitors of slow reacting substance of anaphylaxis (SRS-A) mediated bronchospasm in the GP in vivo. Most representatives of this new class of potential antiallergic/antiinflammatory agents showed potent inhibition of 5-LO activity in rat PMNs. The most potent compound, 2-[[3-(1-hydroxyhexyl)phenoxy]-methyl]quinoline (33), had an I50 of 0.12 microM in the rat PMN 5-LO assay and an I50 of 3.6 microM in the leukotriene-induced contraction of GP lung parenchymal strips, and it also showed 91% inhibition of SRS-A-mediated bronchospasm in the GP in vivo at 10 mg/kg, administered intraduodenally. Some of the compounds in this series were also leukotriene antagonists in vitro, and several of them showed in vivo activity against SRS-A-mediated bronchospasm in the GP.
mesh_terms: D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D010647:Phenyl Ethers; D013189:SRS-A; D001091:Arachidonate Lipoxygenases