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
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
收藏
页码:690 / 705
页数:16
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