Multisubstituted quinoxalines and pyrido[2,3-d]pyrimidines: Synthesis and SAR study as tyrosine kinase c-Met inhibitors

被引：30

作者：

Wu, Kui ^{[1
]}

Ai, Jing ^{[2
]}

Liu, Qiufeng ^{[3
]}

Chen, TianTian ^{[3
]}

Zhao, Ailing ^{[4
]}

Peng, Xia ^{[2
]}

Wang, Yuanxiang ^{[4
]}

Ji, Yinchun ^{[2
]}

Yao, Qizheng ^{[1
]}

Xu, Yechun ^{[3
]}

Geng, Meiyu ^{[2
]}

Zhang, Ao ^{[4
]}

机构：

[1] China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China

[4] Chinese Acad Sci, Shanghai Inst Mat Med, Synthet Organ & Med Chem Lab, Shanghai 201203, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 20期

基金：

中国国家自然科学基金; 美国国家科学基金会;

关键词：

c-Met kinase; 3,5-Diamino-7-trifluoroquinoline; hERG; Antitumor activity; Structure-activity relationship (SAR); SCATTER-FACTOR; GROWTH; METASTASIS; POTENT;

D O I：

10.1016/j.bmcl.2012.08.075

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Two series of new analogues were designed by replacing the quinoline scaffold of our earlier lead 2 (zgw-atinib) with quinoxaline and pyrido[2,3-d]pyrimidine frameworks. Moderate c-Met inhibitory activity was observed in the quinoxaline series. Among the pyrido[2,3-d]pyrimidine series, compounds 13a-c possessing an O-linkage were inactive, whilst the N-linked analogues 15a-c retained c-Met inhibitory potency. Highest activity was observed in the 3-nitrobenzyl analog 15b that showed an IC50 value of 6.5 nM. Further structural modifications based on this compound were undergoing. (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：6368 / 6372

页数：5

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