Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids as leukotriene biosynthesis inhibitors

被引：32

作者：

Kolasa, T ^{[1
]}

Gunn, DE ^{[1
]}

Bhatia, P ^{[1
]}

Woods, KW ^{[1
]}

Gane, T ^{[1
]}

Stewart, AO ^{[1
]}

Bouska, JB ^{[1
]}

Harris, RR ^{[1
]}

Hulkower, KI ^{[1
]}

Malo, PE ^{[1
]}

Bell, RL ^{[1
]}

Carter, GW ^{[1
]}

Brooks, CDW ^{[1
]}

机构：

[1] Abbott Labs, Immunosci Res, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2000年 / 43卷 / 04期

关键词：

D O I：

10.1021/jm9904102

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of heteroarglmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure-activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity, The promising lead, S-(E)-11, inhibited LTB4 biosynthesis in the intact human neutrophil with IC50 of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED50 0.14 mg/kg) and rat anaphylaxis model (ED50 = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE4 biosynthesis (ED50 of 0.1 mg/kg) and eosinophil influx (ED50 of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.

引用

页码：690 / 705

页数：16