Further SAR studies on 3,5-diamino-7-trifluoromethylquinolines as highly potent tyrosine kinase c-Met inhibitors: efforts to correct hERG inhibition

Yuanxiang Wang; Jing Ai; Jinfeng Yue; Xia Peng; Yinchun Ji; Ailing Zhao; Xin Gao; Ying Wang; Yi Chen; Gang Liu; Zhaobing Gao; Meiyu Geng; Ao Zhang

doi:10.1039/C2MD20192E

Further SAR studies on 3,5-diamino-7-trifluoromethylquinolines as highly potent tyrosine kinase c-Met inhibitors: efforts to correct hERG inhibition

Yuanxiang Wang,†^a Jing Ai,†^b Jinfeng Yue,†^b Xia Peng,^b Yinchun Ji,^b Ailing Zhao,^a Xin Gao,^b Ying Wang,^b Yi Chen,^b Gang Liu,^a Zhaobing Gao,*^b Meiyu Geng*^b and Ao Zhang*^a

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* Corresponding authors

^a Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
E-mail: aozhang@mail.shcnc.ac.cn
Fax: +86-21-50806035
Tel: +86-21-50806035

^b Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
E-mail: mygeng@mail.shcnc.ac.cn, zb.gao@mail.shcnc.ac.cn
Fax: +86-21-50806072
Tel: +86-21-50806072

Abstract

A preclinical study on our previously discovered highly potent c-Met inhibitor 1 (zgwatinib) demonstrated its significant toxicity, and a SAR campaign was conducted to finely tune down the hERG inhibition without affecting the c-Met potency. Compounds 11, 12 and 39 stood out as new c-Met inhibitors with IC₅₀ values of <3.0 nM and being nearly inactive against hERG channels.

MedChemComm

Further SAR studies on 3,5-diamino-7-trifluoromethylquinolines as highly potent tyrosine kinase c-Met inhibitors: efforts to correct hERG inhibition

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Further SAR studies on 3,5-diamino-7-trifluoromethylquinolines as highly potent tyrosine kinase c-Met inhibitors: efforts to correct hERG inhibition

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