Identification of novel pyrazole acid antagonists for the EP1 receptor

被引：29

作者：

McKeown, Stephen C.

Hall, Adrian

Giblin, Gerard M. P.

Lorthioir, Olivier

Blunt, Richard

Lewell, Xiao Q.

Wilson, Richard J.

Brown, Susan H.

Chowdhury, Anita

Coleman, Tanya

Watson, Stephen P.

Chessell, Iain P.

Pipe, Adrian

Clayton, Nick

Goldsmith, Paul

机构：

[1] GlaxoSmithKline Inc, Discovery Res, Harlow CM19 5AW, Essex, England

[2] GlaxoSmithKline Inc, Neurol & Gastrointestinal Ctr Excellence Drug Dis, Harlow CM19 5AW, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 18期

关键词：

EP1; antagonist; pain; pyrazole; prostanoid;

D O I：

10.1016/j.bmcl.2006.06.086

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE(2) mediated pain. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：4767 / 4771

页数：5

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