Discovery of brain penetrant, soluble, pyrazole amide EP1 receptor antagonists

被引：12

作者：

Hall, Adrian ^{[1
]}

Billinton, Andy ^{[1
]}

Bristow, Alan K. ^{[2
]}

Brown, Susan H. ^{[1
]}

Chowdhury, Anita ^{[1
]}

Cutler, Leanne ^{[1
]}

Giblin, Gerard M. P. ^{[1
]}

Goldsmith, Paul ^{[1
]}

Hayhow, Thomas G. ^{[1
]}

Kilford, Ian R. ^{[1
]}

Naylor, Alan ^{[1
]}

Passingham, Barry ^{[1
]}

Rawlings, D. Anthony ^{[1
]}

机构：

[1] GlaxoSmithKline, Neurolosci Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England

[2] Pharmaceut Dev, Harlow CM19 5AW, Essex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 14期

关键词：

non-acidic EP1 antagonist; amide EP1 antagonist; brain penetration; CNS penetration; solubility; improved solubility; oral exposure; oral absorption;

D O I：

10.1016/j.bmcl.2008.05.118

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We describe the discovery of a series of pyrazole amide EP1 receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8: 1-2.0: 1 in addition to good solubility and metabolic stability. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4027 / 4032

页数：6

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