Design and synthesis of o-trifluoromethylbiphenyl substituted 2-amino-nicotinonitriles as inhibitors of farnesyltransferase

Bioorg Med Chem Lett. 2005 Jan 3;15(1):153-8. doi: 10.1016/j.bmcl.2004.10.014.

Abstract

A non-methionine FT inhibitor lead structure (1) was designed through computer modeling of the peptidomimetic FT inhibitor ABT839. Optimization of this lead resulted in compounds 2e and 2g, with FT IC(50) values of 1.3 and 1.8 nM, GGT IC(50) of 1400 nM, and EC(50) (Ras processing) values of 13 and 11 nM, respectively.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Biphenyl Compounds / chemical synthesis*
  • Biphenyl Compounds / pharmacology*
  • Computer Simulation
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Farnesyltranstransferase
  • Imidazoles
  • Models, Molecular
  • Molecular Mimicry
  • Nicotinic Acids / chemical synthesis*
  • Nicotinic Acids / pharmacology*
  • Nitriles

Substances

  • 4-(3-biphenyl-2-yl-1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-prop-2-ynyl)-1-yl-benzonitrile
  • Biphenyl Compounds
  • Enzyme Inhibitors
  • Imidazoles
  • Nicotinic Acids
  • Nitriles
  • Alkyl and Aryl Transferases
  • Farnesyltranstransferase