Discovery of N-(benzyloxy)-1, 3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: Lv, Xian-Hai; Ren, Zi-Li; Zhou, Ben-Guo; Li, Qing-Shan; Chu, Ming-Jie; Liu, Dao-Hong; Mo, Kai; Zhang, Li-Song; Yao, Xiao-Kang; Cao, Hai-Qun
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 19(2016)
• Page Start: 4652
• Page End: 4659
• Publication Date: 2016-10-01
• Subjects: MEK mitogen-activated protein kinase -- BRAF V-RAF murine sarcoma viral oncogene homologue B1 -- ERK extracellular regulated kinase -- BRAFV600E V600E mutant BRAF -- BRAFV600K V600K mutant BRAF -- IC50 half maximal inhibitory concentration -- GI50 the concentration that causes 50% growth inhibition -- SAR structure–activity relationship; Anti-cancer activity -- Inhibitors -- MEK -- Molecular docking -- Pyrazole -- QSAR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.08.002
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Twenty N -(benzyloxy)-1, 3-diphenyl-1 H -pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, compound7b showed the most potent inhibitory activity with IC50 of 91 nM for MEK1 and GI50 value of 0.26 μM for A549 cells. Abstract: 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. Twenty N -(benzyloxy)-1, 3-diphenyl-1 H -pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound7b showed the most potent inhibitory activity with IC50 of 91 nM for MEK1 and GI50 value 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.