Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor

被引：66

作者：

Abdi, Muna H. ^{[1
]}

Beswick, Paul J. ^{[1
]}

Billinton, Andy ^{[1
]}

Chambers, Laura J. ^{[1
]}

Charlton, Andrew ^{[1
]}

Collins, Sue D. ^{[1
]}

Collis, Katharine L. ^{[1
]}

Dean, David K. ^{[1
]}

Fonfria, Elena ^{[1
]}

Gleave, Robert J. ^{[1
]}

Lejeune, Clarisse L. ^{[1
]}

Livermore, David G. ^{[1
]}

Medhurst, Stephen J. ^{[1
]}

Michel, Anton D. ^{[1
]}

Moses, Andrew P. ^{[1
]}

Page, Lee ^{[1
]}

Patel, Sadhana ^{[1
]}

Roman, Shilina A. ^{[1
]}

Senger, Stefan ^{[1
]}

Slingsby, Brian ^{[1
]}

Steadman, Jon G. A. ^{[1
]}

Stevens, Alexander J. ^{[1
]}

Walter, Daryl S. ^{[1
]}

机构：

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 17期

关键词：

P2X7; Antagonist; Pain; SAR; PAIN; HYPERALGESIA; MODEL;

D O I：

10.1016/j.bmcl.2010.07.033

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5080 / 5084

页数：5

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