Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK

Bioorg Med Chem. 2016 Oct 1;24(19):4652-4659. doi: 10.1016/j.bmc.2016.08.002. Epub 2016 Aug 3.

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-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26μM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.

Keywords: Anti-cancer activity; Inhibitors; MEK; Molecular docking; Pyrazole; QSAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Signaling System / drug effects
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology*
  • Quantitative Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Biphenyl Compounds
  • Protein Kinase Inhibitors
  • Pyrazoles
  • diphenyl
  • MAP Kinase Kinase 1