4-(嘧啶-2-氨基)苯甲酰胺衍生物的设计、合成及Hedgehog信号通路抑制研究  

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

作　　者：张连第[1,2] 辛敏行[2,3] 文珺[2] 唐锋[2] 涂崇兴[2] 沈晗[2] 韦萍[1] 

机构地区：[1]南京工业大学生物与制药工程学院,南京211800 [2]江苏先声药业有限公司江苏省抗肿瘤分子靶向药物重点实验室,南京210042 [3]西安交通大学医学部药学院,西安710061

出　　处：《有机化学》2014年第7期1407-1416,共10页Chinese Journal of Organic Chemistry

基　　金："重大新药创制"科技重大专项基金(No.2011ZX09401-008)资助项目~~

摘　　要：Hedgehog信号通路是近年来抗肿瘤靶向治疗药物研究的一个新热点.本研究以4-(嘧啶-2-氨基)苯甲酰胺为母核,基于先导化合物1的构效关系,设计并合成了14个未见文献报道的4-(嘧啶-2-氨基)苯甲酰胺类Hedgehog信号通路抑制剂,并进行了初步的抗Hedgehog信号通路活性筛选.结果表明:所合成的化合物均表现出较好的Hedgehog信号通路抑制活性,其中化合物8e的活性最好,IC50为5.0 nmol?L-1,高于阳性药GDC-0449;同时在体内药代性质研究中,8e相比化合物1,药代性质均有所改善.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 previ- ously 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 IC50 value of 5.0 nmol.L-1, more potent than GDC-0449. Likewise, compound 8e displayed improved pharmacokinetic properties.

关 键 词：HEDGEHOG信号通路 4-(嘧啶-2-氨基)苯甲酰胺 合成 抑制活性 

分 类 号：O626[理学—有机化学] TQ460.1[理学—化学]