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.
出处
《有机化学》
SCIE
CAS
CSCD
北大核心
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~~
