Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist

被引：36

作者：

Brotherton-Pleiss, Christine E. ^{[1
]}

Dillon, Michael P. ^{[1
]}

Ford, Anthony P. D. W. ^{[2
]}

Gever, Joel R. ^{[2
]}

Carter, David S. ^{[1
]}

Gleason, Shelley K. ^{[1
]}

Lin, Clara J. ^{[1
]}

Moore, Amy G. ^{[1
]}

Thompson, Anthony W. ^{[1
]}

Villa, Marzia ^{[1
]}

Zhai, Yansheng ^{[1
]}

机构：

[1] Roche Palo Alto, Dept Med Chem, Palo Alto, CA 94304 USA

[2] Roche Palo Alto, Dept Biochem Pharmacol, Palo Alto, CA 94304 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 03期

关键词：

P2X(3); Ion channel; RO-85; Inflammatory pain; Neuropathic pain; Drug-like; P2X(3) receptor antagonist; P2X(2/3) RECEPTORS; PAIN; SPINORPHIN; CHANNELS; A-317491; MICE; RAT;

D O I：

10.1016/j.bmcl.2009.12.044

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Despite the extensive literature describing the role of the ATP-gated P2X(3) receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X(3) antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1031 / 1036

页数：6

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