Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors.
Design, Synthesis and Biological Evaluation of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-4-substituted-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors.
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6-(2,6-二氯-3,5-二甲氧基苯基)-4-取代-1H-吲唑作为有效成纤维细胞生长因子受体抑制剂的设计、合成和生物学评价
DOI：
10.3390/molecules21101407
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发表时间：
2016-10-23
期刊：
影响因子：
--
通讯作者：
Xiong B
中科院分区：
文献类型：
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作者：
Zhang Z;Zhao D;Dai Y;Cheng M;Geng M;Shen J;Ma Y;Ai J;Xiong B
酪氨酸激酶成纤维细胞生长因子受体（FGFR）在多种癌症类型中是异常的，是癌症治疗的有希望的靶点。本文报道了一系列新的6-（2，6-二氯-3，5-二甲氧基苯基）-4-取代-1H-吲唑衍生物的设计、合成和生物活性评价。化合物6-（2，6-二氯-3，5-二甲氧基苯基）-N-苯基-1H-吲唑-4-甲酰胺（10a）被鉴定为有效的FGFR 1抑制剂，具有良好的酶抑制作用。进一步基于结构的优化显示，6-（2，6-二氯-3，5-二甲氧基苯基）-N-（3-（4-甲基哌嗪-1-基）苯基）-1H-吲唑-4-甲酰胺（13 a）是该系列中最有效的FGFR 1抑制剂，其酶抑制活性IC 50值约为30.2 nM。
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.