Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK.
Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK.
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DOI：
10.1016/j.bmc.2016.08.002
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发表时间：
2016-10
影响因子：
3.5
通讯作者：
Xianhai Lv;Zi-Li Ren;Ben-Guo Zhou;Qingshan Li;M. Chu;Dao-Hong Liu;Kai‐For Mo;Li-Song Zhang;Xiao-Kang Yao;H. Cao
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文献类型：
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作者：
Xianhai Lv;Zi-Li Ren;Ben-Guo Zhou;Qingshan Li;M. Chu;Dao-Hong Liu;Kai‐For Mo;Li-Song Zhang;Xiao-Kang Yao;H. Cao
丝裂原活化蛋白激酶（Mitogen activated protein kinase， MAPK）信号转导通路在肿瘤发生和肿瘤发展中起重要作用。MEK抑制剂已被证明在阻断MAPK通路激活方面具有显著的临床益处，并且可能在BRAF抑制剂耐药时阻断MAPK通路的再激活。设计合成了20个n -（苯氧基）-1,3-二苯基- 1h -吡唑-4-羧酰胺衍生物作为MEK抑制剂，并对其生物活性进行了评价。其中化合物7对MEK1的ic50值为91 nM，对A549细胞的gi50值为0.26 μM，抑制活性最强。通过SAR分析和对接仿真，为进一步优化结构提供重要的药效团线索。
Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. TwentyN-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound7bshowed the most potent inhibitory activity with IC50of 91 nM for MEK1 and GI50value of 0.26 μM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.