Anthranilic acid derivatives as novel ligands for farnesoid X receptor (FXR)

Bioorg Med Chem. 2014 Apr 15;22(8):2447-60. doi: 10.1016/j.bmc.2014.02.053. Epub 2014 Mar 15.


Nuclear farnesoid X receptor (FXR) has important physiological roles in various metabolic pathways including bile acid, cholesterol and glucose homeostasis. The clinical use of known synthetic non-steroidal FXR ligands is restricted due to toxicity or poor bioavailability. Here we report the development, synthesis, in vitro activity and structure-activity relationship (SAR) of anthranilic acid derivatives as novel FXR ligands. Starting from a virtual screening hit we optimized the scaffold to a series of potent partial FXR agonists with appealing drug-like properties. The most potent derivative exhibited an EC50 value of 1.5±0.2 μM and 37±2% maximum relative FXR activation. We investigated its SAR regarding polar interactions with the receptor by generating derivatives and computational docking.

Keywords: Bile acids; Farnesoid X receptor; Glucose homeostasis; Metabolic disorder; Nuclear receptor.

MeSH terms

  • Binding Sites
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Structure-Activity Relationship
  • ortho-Aminobenzoates / chemical synthesis
  • ortho-Aminobenzoates / chemistry
  • ortho-Aminobenzoates / metabolism*


  • Ligands
  • Receptors, Cytoplasmic and Nuclear
  • ortho-Aminobenzoates
  • farnesoid X-activated receptor
  • anthranilic acid