Leukotriene D4 antagonists and 5-lipoxygenase inhibitors. Synthesis of benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters.
A series of novel benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters has been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte 5-lipoxgenase (LO) in vitro and as inhibitors of leukotriene D4 (LTD4) and ovalbumin (OA) induced bronchospasm in the guinea pig (GP) in vivo. In general, inhibitory activity against 5-LO, LTD4, and OA was broadest for benzthiazole-containing analogues (benzthiazole greater than benzimidazole much greater than benzoxazole, benzofuran). The most potent 5-LO inhibitor, 4-[[3-(2-benzthiazolylmethoxy)-phenyl]hydroxyamino]-4-oxobutanoic acid methyl ester (7), had an IC50 of 0.36 microM. Compound 7, however, was inactive vs. OA. The most potent compound in vivo, 4-[[3-[(1-methyl-2-benzimidazolyl)methoxy]phenyl]-amino] -4-oxobutanoic acid methyl ester 4, inhibited both LTD4- and OA-induced bronchospasm by 83% and 60%, respectively, at 50 mg/kg intraduodenally. Compound 4 was studied in the Ames assay employing five strains of bacteria (TA1535, TA1537, TA1538, TA98, and TA100) with and without S-9 rat liver enzyme metabolic activation, and there was no significant number of reversions noted.
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009504:Neutrophils / Q000201:enzymology; D051381:Rats; D013189:SRS-A / Q000037:antagonists & inhibitors*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D005227:Fatty Acids; D006571:Heterocyclic Compounds; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; D001091:Arachidonate Lipoxygenases; D001094:Arachidonate 5-Lipoxygenase