Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties

Bioorg Med Chem. 2015 Jul 1;23(13):3490-8. doi: 10.1016/j.bmc.2015.04.035. Epub 2015 Apr 18.


The ligand activated transcription factor farnesoid X receptor (FXR) is a crucial regulator of several metabolic and inflammatory pathways and its activation by agonistic ligands seems a valuable therapeutic approach for many disorders. Most known non-steroidal FXR agonists however, have limitations that hinder their clinical development and novel FXR ligands are required. Evaluation of the co-crystal structures of the widely used FXR agonist GW4064 and related compounds in complex with the FXR ligand binding domain indicated that their disubstituted isoxazole moiety is especially relevant for FXR activation. By investigation of GW4064-fragments missing the aromatic tail, we discovered a highly potent and soluble partial FXR agonist (14, ST-1892) as well as a fluorescent FXR ligand (15) as potential pharmacological tool.

Keywords: FXR agonists; Farnesoid X receptor; Fluorescent FXR ligand; Metabolic disorders; Nuclear receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Gene Expression
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Hydrolysis
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacology
  • Ligands
  • Molecular Docking Simulation
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Structure-Activity Relationship
  • Transfection


  • Isoxazoles
  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • GW 4064