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Molecules 2016, 21(10), 1407; doi:10.3390/molecules21101407

Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors

1
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
2
Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
3
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
*
Authors to whom correspondence should be addressed.
Academic Editor: James W. Leahy
Received: 10 September 2016 / Revised: 13 October 2016 / Accepted: 17 October 2016 / Published: 23 October 2016
(This article belongs to the Special Issue Kinase Inhibitor Chemistry)
View Full-Text   |   Download PDF [3971 KB, uploaded 24 October 2016]   |  

Abstract

Tyrosine kinase fibroblast growth factor receptor (FGFR), which is aberrant in various cancer types, is a promising target for cancer therapy. Here we reported the design, synthesis, and biological evaluation of a new series of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazole derivatives as potent FGFR inhibitors. The compound 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-phenyl-1H-indazole-4-carboxamide (10a) was identified as a potent FGFR1 inhibitor, with good enzymatic inhibition. Further structure-based optimization revealed that 6-(2,6-dichloro-3,5-dimethoxyphenyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1H-indazole-4-carboxamide (13a) is the most potent FGFR1 inhibitor in this series, with an enzyme inhibitory activity IC50 value of about 30.2 nM. View Full-Text
Keywords: cancer; FGFR; inhibitor; 4-substituted-1H-indazole cancer; FGFR; inhibitor; 4-substituted-1H-indazole
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Zhang, Z.; Zhao, D.; Dai, Y.; Cheng, M.; Geng, M.; Shen, J.; Ma, Y.; Ai, J.; Xiong, B. Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors. Molecules 2016, 21, 1407.

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