Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents

Bioorg Med Chem. 2013 Mar 1;21(5):1284-304. doi: 10.1016/j.bmc.2012.12.035. Epub 2013 Jan 3.

Abstract

The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzofurans / chemistry
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology
  • Melanoma / metabolism
  • Melanoma / pathology
  • Naphthols / chemical synthesis
  • Naphthols / chemistry*
  • Naphthols / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / metabolism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology

Substances

  • 1-(6-(2-(4-(2-dimethylaminoethoxy)phenyl)-5-(pyridin-4-yl)-1H-imidazol-4-yl)benzo(b)thiophen-3-yl)-2,2,2-trifluoroethanol
  • 6-(2-(4-(2-dimethylaminoethoxy)phenyl)-5-pyridin-4-yl-3H-imidazol-4-yl)naphthalen-1-ol
  • Benzofurans
  • Imidazoles
  • Naphthols
  • Protein Kinase Inhibitors
  • Thiophenes
  • benzothiophene
  • imidazole
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • benzofuran