Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors

J Med Chem. 2004 Jan 29;47(3):612-26. doi: 10.1021/jm030434f.

Abstract

A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / chemistry
  • Alkyl and Aryl Transferases / metabolism
  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacokinetics
  • Benzamides / pharmacology
  • Biological Availability
  • Cell Membrane Permeability
  • Crystallography, X-Ray
  • Dogs
  • Drug Design
  • Farnesyltranstransferase
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Nitriles / chemical synthesis*
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology
  • Structure-Activity Relationship

Substances

  • 5-cyano-2-((4-cyanophenyl)-(3-methyl-3H-imidazol-4-yl)methoxymethyl)-N-phenylbenzamide
  • Benzamides
  • Imidazoles
  • Nitriles
  • Alkyl and Aryl Transferases
  • geranylgeranyltransferase type-I
  • Farnesyltranstransferase