Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist
Discovery and optimization of RO-85, a novel drug-like, potent, and selective P2X3 receptor antagonist
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DOI：
10.1016/j.bmcl.2009.12.044
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发表时间：
2010-02-01
影响因子：
2.7
通讯作者：
Zhai, Yansheng
中科院分区：
文献类型：
--
作者：
Brotherton-Pleiss, Christine E.;Dillon, Michael P.;Zhai, Yansheng
尽管有大量文献描述了 ATP 门控 P2X(3) 受体在各种生理过程中的作用，但拮抗剂作为治疗剂的潜力由于缺乏药物样选择性分子而受到限制。在本文中，我们报告了 RO-85 的发现和优化，RO-85 是一种新型药物样、有效的选择性 P2X(3) 拮抗剂。对罗氏化合物集合进行高通量筛选，从大型平行合成库中鉴定出一小部分热门杂环酰胺系列。通过高通量合成促进的快速优化，重点关注增加效力和改善药物相似性，最终发现了 RO-85。 (C) 2009 Elsevier Ltd. 保留所有权利。
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.