Xin Minhang, Zhang Liandi, Wen Jun, Shen Han, Liu Zhaoyu, Zhao Xinge, Jin Qiu, Wang Mengyu, Cheng Lingfei, Huang Wei, Tang Feng
Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, PR China.
Jiangsu Simcere Pharmaceutical Co. Ltd, No. 699-18, Xuan Wu District, Nanjing 210042, PR China.
Bioorg Med Chem. 2016 Mar 1;24(5):1079-88. doi: 10.1016/j.bmc.2016.01.034. Epub 2016 Jan 19.
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 1.44nM 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.
在本研究中，通过氟扫描策略设计了一系列新型含三氟甲基的4-(2-嘧啶基氨基)苯甲酰胺衍生物。采用Gli-荧光素酶报告基因法评估了它们对Hh信号通路的抑制活性。讨论了全面的构效关系，发现几种衍生物对Hh信号通路的抑制活性比阳性药物维莫德吉更强。化合物13d是最有效的化合物，对Hh信号通路的IC50为1.44nM，并且在体内药代动力学性质研究中也表现出最佳的药代动力学性质，值得作为未来进一步研究的理想先导化合物。
