Synthesis of [[(naphthalenylmethoxy)- and [[(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters. A novel series of leukotriene D4 antagonists and 5-lipoxygenase inhibitors.
A series of novel [[(naphthalenylmethoxy)- and [[(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters have been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte (PMN) 5-lipoxygenase (LO) in vitro and as inhibitors of ovalbumin (OA) and leukotriene D4 (LTD4) induced bronchospasm in the guinea pig (GP) in vivo. Many naphthalenyl compounds were potent inhibitors of 5-LO, and several quinolinyl compounds were potent inhibitors of LTD4-mediated bronchospasms in the GP. The most potent naphthalenyl compound, 4-[[3-(2-naphthalenylmethoxy)phenyl]hydroxyamino]-4-oxobutanoic acid, methyl ester (6v), had an IC50 of 0.6 microM in the 5-LO assay. The most potent compound in vivo, 4-[[3-(2-quinolinylmethoxy)phenyl]hydroxyamino]-4-oxobutanoic acid, methyl ester (6e), had ED50's of 3.3 mg/kg and 27.4 mg/kg (intraduodenally) against LTD4- and OA-induced bronchospasm, respectively. When tested as an antagonist of LTD4-induced contraction of isolated GP tracheal spiral strips, 6e was shown to be a competitive inhibitor with a pKB value of 5.33.
D000818:Animals; D001091:Arachidonate Lipoxygenases; D001980:Bronchi / Q000187:drug effects; D006168:Guinea Pigs; D016859:Lipoxygenase Inhibitors; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology; D010047:Ovalbumin / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects
D016859:Lipoxygenase Inhibitors; D008738:Methyl Ethers; D009281:Naphthalenes; D011804:Quinolines; D013189:SRS-A; D010047:Ovalbumin; D001091:Arachidonate Lipoxygenases