Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Nav1.7 antagonists
Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Nav1.7 antagonists
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DOI：
10.1016/j.bmcl.2012.01.015
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发表时间：
2012-03-01
影响因子：
2.7
通讯作者：
DiMauro, Erin F.
中科院分区：
文献类型：
--
作者：
Chakka, Nagasree;Bregman, Howie;DiMauro, Erin F.
在这里，我们描述了新的有效的吡咯并嘧啶Na（V）1.7拮抗剂的发现，优化和结构-活性关系。分子的吡咯并嘧啶核心、头部和尾部基团的命中-先导SAR研究导致将吡咯并嘧啶48鉴定为异常有效的Na（v）1.7阻断剂，相对于我们的命中分子和吡唑并嘧啶8具有良好的hERG选择性和改善的微粒体稳定性，作为未来优化工作的有希望的起点。出版社：Elsevier Ltd
Herein we describe the discovery, optimization, and structure-activity relationships of novel potent pyrrolopyrimidine Na(v)1.7 antagonists. Hit-to-lead SAR studies of the pyrrolopyrimidine core, head, and tail groups of the molecule led to the identification of pyrrolopyrimidine 48 as exceptionally potent Na(v)1.7 blocker with good selectivity over hERG and improved microsomal stability relative to our hit molecule and pyrazolopyrimidine 8 as a promising starting point for future optimization efforts. Published by Elsevier Ltd.