Structure based design and syntheses of amino-1H-pyrazole amide derivatives as selective Raf kinase inhibitors in melanoma cells

Bioorg Med Chem. 2011 Mar 15;19(6):1915-23. doi: 10.1016/j.bmc.2011.01.067. Epub 2011 Feb 3.

Abstract

The synthesis of a novel series of N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl amide derivatives 6a-o, 7a-s and their antiproliferative activities against A375P melanoma cell line were described. Most compounds showed competitive antiproliferative activities to sorafenib, the reference standard. Among them, N-(5-amino-1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido)-2-methylbenzamide 7c exhibited potent activities (GI(50)=0.27 μM). Especially, 7c was found to be a potent and selective B-Raf V600E and C-Raf inhibitor (IC(50)=0.26 μM, IC(50)=0.11 μM, respectively), showing a possibility as melanoma therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry*
  • Amides / therapeutic use
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / therapeutic use
  • Benzenesulfonates / chemistry
  • Binding Sites
  • Cell Line, Tumor
  • Computer Simulation
  • Humans
  • Melanoma / drug therapy*
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles / chemistry*
  • Pyridines / chemistry
  • Sorafenib
  • Structure-Activity Relationship
  • raf Kinases / antagonists & inhibitors*
  • raf Kinases / metabolism

Substances

  • Amides
  • Antineoplastic Agents
  • Benzenesulfonates
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Niacinamide
  • pyrazole
  • Sorafenib
  • raf Kinases