Synthesis and biological evaluation of novel 6,11-dihydro-5H-benzo[e] pyrimido- [5,4-b][1,4]diazepine derivatives as potential c-Met inhibitors

被引：17
|
作者：
Huang, Daowei [1 ,2 ]
Huang, Lei [1 ,2 ]
Zhang, Qingwei [1 ,2 ]
Li, Jianqi [1 ,2 ]
机构：
[1] Shanghai Inst Pharmaceut Ind, Novel Technol Ctr Pharmaceut Chem, Shanghai 201203, Peoples R China
[2] Shanghai Engn Res Ctr Pharmaceut Proc, Shanghai 201203, Peoples R China
来源：
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 140卷
基金：
中国国家自然科学基金;
关键词：
c-Met; tyrosine kinase; Diazepine derivatives; Synthesis; Antitumor; RECEPTOR TYROSINE KINASE; GROWTH-FACTOR RECEPTOR; SMALL-MOLECULE INHIBITOR; ANTITUMOR-ACTIVITY; DUAL INHIBITORS; IN-VIVO; DESIGN; MOIETY; DISCOVERY; BEARING;
D O I：
10.1016/j.ejmech.2017.08.060
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Over expression of c-Met tyrosine kinase is known to promote tumorigenesis and metastasis, as well as to cause therapeutic resistance. Herein a series of novel 6,11-dihydro-5H-benzo[e]pyrimido[5,4-b][1,4] diazepine derivatives were designed, synthesised and evaluated for their c-Met kinase inhibition. Compounds 17e, 17f, 18a, and 18b were further examined for their anti-proliferative activities against four typical cancer cell lines (PC-3, Panc-1, HepG2, and Caki-1). The promising compound 17f was identified as a multi-target receptor tyrosine kinase inhibitor, which also displayed favourable pharmacokinetic properties in rats, had an acceptable safety profile in preclinical studies, and significant anti tumour activity in the Caki-1 tumour xenograft model. (C) 2017 Published by Elsevier Masson SAS.
引用
收藏
页码：212 / 228
页数：17
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