Optimization of a novel class of benzimidazole-based farnesoid X receptor (FXR) agonists to improve physicochemical and ADME properties

Bioorg Med Chem Lett. 2011 Feb 15;21(4):1134-40. doi: 10.1016/j.bmcl.2010.12.123. Epub 2010 Dec 31.

Abstract

Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.

MeSH terms

  • 4-Aminobenzoic Acid / chemical synthesis
  • 4-Aminobenzoic Acid / chemistry
  • 4-Aminobenzoic Acid / pharmacokinetics
  • Administration, Oral
  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacokinetics
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver / metabolism
  • Molecular Conformation
  • Rats
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Structure-Activity Relationship
  • para-Aminobenzoates*

Substances

  • 4-(2-(2-(4-chlorophenyl)-5,6-difluorobenzoimidazol-1-yl)-2-cyclohexylacetylamino)-3-fluorobenzoic acid
  • Benzimidazoles
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, LDL
  • para-Aminobenzoates
  • farnesoid X-activated receptor
  • benzimidazole
  • 4-Aminobenzoic Acid