Synthesis of [[(naphthalenylmethoxy)- and -(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters. A novel series of leukotriene D4 antagonists and 5-lipoxygenase inhibitors

• Published in: Journal of medicinal chemistry Vol. 29; no. 8; pp. 1429 - 1435
• Main Authors: Musser, John H, Kubrak, Dennis M, Chang, Joseph, Lewis, Alan J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1986
• Subjects: Animals; Arachidonate Lipoxygenases; Bronchi - drug effects; Chemistry; Exact sciences and technology; Guinea Pigs; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Lipoxygenase Inhibitors; Male; Methyl Ethers - pharmacology; Muscle Contraction - drug effects; Naphthalenes - chemical synthesis; Naphthalenes - pharmacology; Neutrophils - enzymology; Organic chemistry; Ovalbumin - antagonists & inhibitors; Preparations and properties; Quinolines - chemical synthesis; Quinolines - pharmacology; Rats; SRS-A - antagonists & inhibitors; Structure-Activity Relationship; Trachea - drug effects; Aliphatic compound; Nitrogen heterocycle; Saturated compound; Bicyclic compound; Enzyme inhibitor; Dicarboxylic acid; Aromatic compound; Antagonist; Lipoxygenase; Condensed benzenic compound; Biological activity; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00158a019

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.