LEUKOTRIENE-D4 ANTAGONISTS AND 5-LIPOXYGENASE INHIBITORS - SYNTHESIS OF BENZOHETEROCYCLIC [(METHOXYPHENYL)AMINO]OXOALKANOIC ACID-ESTERS

被引:30
作者
MUSSER, JH [1 ]
KUBRAK, DM [1 ]
CHANG, J [1 ]
DIZIO, SM [1 ]
HITE, M [1 ]
HAND, JM [1 ]
LEWIS, AJ [1 ]
机构
[1] WYETH LABS INC, POB 8299, PHILADELPHIA, PA 19101 USA
关键词
D O I
10.1021/jm00385a024
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 > benzimidazole > .mchgt. benzoxazole, benzofuran). The most potent 5-LO inhibitor, 4-[[3-(2-benzthiazolylmethoxy)-phenyl]hydroxyamino]-4-oxobutanoic acid methy ester (7), had an IC50 of 0.36 .mu.M. Compound 7, however, was inactive vs. OA. The most potent compound in vivo, 4-[[3-[(1-methyl-2-bezimidazolyl)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.
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页码:400 / 405
页数:6
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