Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened
Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened
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DOI：
10.1021/ml2002423
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发表时间：
2012-02-01
影响因子：
4.2
通讯作者：
Tkalcevic, George T.
中科院分区：
文献类型：
--
作者：
Munchhof, Michael J.;Li, Qifang;Tkalcevic, George T.
由于越来越多的证据表明，Hedgehog信号通路抑制剂有可能为患者提供有希望的治疗选择，因此在肿瘤学领域引起了极大的兴趣。在此，我们描述了克服铅结构I固有问题的发现策略，这些问题导致鉴定出平滑抑制剂14（2R,4R)-2-（1h -苯并[d]咪唑-2-基）-1-甲基哌啶-4-基）-3-（4-氰苯基）尿素（nf - 04449913,26），该抑制剂已进入人体临床研究。
Inhibitors of the Hedgehog signaling pathway have generated a great deal of interest in the oncology area due to the mounting evidence of their potential to provide promising therapeutic options for patients. Herein, we describe the discovery strategy to overcome the issues inherent in lead structure I that resulted in the identification of Smoothened inhibitor 14(2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea (PF-04449913, 26), which has been advanced to human clinical studies.