Synthesis of [[(naphthalenylmethoxy)- and -(quinolinylmethoxy)phenyl]amino]oxoalkanoic acid esters. A novel series of leukotriene D4 antagonists and 5-lipoxygenase inhibitors
Citations Over TimeTop 10% of 1986 papers
Abstract
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.
Related Papers
- → Lipoxygenase inhibitors from natural plant sources. Part 1: Medicinal plants with inhibitory activity on arachidonate 5‐lipoxygenase and 5‐lipoxygenase[sol ]cyclooxygenase(2005)125 cited
- → 5-Lipoxygenase: Regulation and possible involvement in atherosclerosis(2007)70 cited
- → Targeting 5-Lipoxygenase Signaling Pathways to Reverse Drug Resistance in Cancer(2006)1 cited
- → Two Types of Arachidonate 12-Lipoxygenase Demonstrated by Enzymological Immunological and Molecular Biological Studies(1991)
- → Arachidonate 5-Lipoxygenase(2020)