Synthesis and pharmacological evaluation of trifluoromethyl containing 4-(2-pyrimidinylamino)benzamides as Hedgehog signaling pathway inhibitors

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• 作者：Minhang Xin^a ; ^{xmhcpu@163.com" class="auth_mail" title="E-mail the corresponding author} ; Liandi Zhang^b ; Jun Wen^b ; Han Shen^b ; Zhaoyu Liu^b ; Xinge Zhao^b ; Qiu Jin^b ; Mengyu Wang^b ; Lingfei Cheng^b ; Wei Huang^b ; Feng Tang^b
• 关键词：Hedgehog signaling pathway inhibitors ; 4-(2-Pyrimidinylamino)benzamide ; Trifluoromethyl ; SAR ; In vivo
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 March 2016
• 年：2016
• 卷：24
• 期：5
• 页码：1079-1088
• 全文大小：3083 K

文摘

In present study, a series of novel containing trifluoromethyl 4-(2-pyrimidinylamino)benzamide derivatives were designed by the fluorine scan strategy. Their Hh signaling inhibitory activities were evaluated by Gli-luciferase reporter method. The comprehensive SAR was discussed and several derivatives were found to display more potent Hh signaling inhibitory activity than positive drug vismodegib. Compound 13d was the most potent compound with IC₅₀ of 1.44 nM against Hh signaling pathway and also exhibited optimal PK properties in the in vivo PK properties study, deserved as an ideal lead compound for further study in future.