4-(Pyrimidin-2-ylamino)benzamide Derivatives：Design, Synthesis, and Hedgehog Signaling Pathway Inhibition Study

Hedgehog signaling pathway is a new therapeutic target for interventional cancer treatment.A novel series of 4-(pyrimidin-2-ylamino)benzamide derivatives were designed as hedgehog signaling pathway inhibitors based on our previously reported lead compound 1 and its structure activity relationship.Fourteen compounds were synthesized and the inhibitory effects on hedgehog signaling pathway of these compounds were evaluated.The results demonstrated that all the compounds presented good potency against hedgehog signaling pathway, and compound 8e was the most potent one with an IC 50 value of 5.0 nmol•L -1 , more potent than GDC-0449.Likewise, compound 8e displayed improved pharmacokinetic properties. Keywords hedgehog signaling pathway; 4-(pyrimidin-2-ylamino)benzamide; synthesis; inhibitionHedgehog (Hh)信号通路是哺乳动物体内一条非常 重要的通路, 控制着细胞的生长和存活.在胚胎发育过 程中 Hh 通路参与细胞的分化增殖和器官形成; 在成人 体内 Hh 通路则与组织创伤修复、干细胞维系等密切相 关 [1] .Hh 信号转导通路主要由分泌型糖蛋白配体 Hh、 跨 膜蛋白受体 Ptch1、跨膜蛋白 Smo 和核转录因子 Gli 等 相关蛋白组成.