Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands

J Med Chem. 2014 Oct 23;57(20):8477-95. doi: 10.1021/jm501273r. Epub 2014 Oct 9.


Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors. Because endogenous bile acids often target both receptor families, the development of selective ligands has been proven difficult, exposing patients to side effects linked to an unwanted activation of one of the two receptors. In the present study, we describe a novel library of semisynthetic bile acid derivatives obtained by modifications on the cholane scaffold. The pharmacological characterization of this library led to the discovery of 7α-hydroxy-5β-cholan-24-sulfate (7), 6β-ethyl-3α,7β-dihydroxy-5β-cholan-24-ol (EUDCOH, 26), and 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (NorECDCOH, 30) as novel ligands for FXR and GP-BAR1 that might hold utility in the treatment of FXR and GP-BAR1 mediated disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / chemistry*
  • Chemistry Techniques, Synthetic
  • Cholanes / chemistry*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • HEK293 Cells / drug effects
  • Hep G2 Cells / drug effects
  • Humans
  • Ligands
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Molecular Targeted Therapy
  • Pruritus / drug therapy
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Bile Acids and Salts
  • Cholanes
  • GPBAR1 protein, human
  • Gpbar1 protein, mouse
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries
  • farnesoid X-activated receptor