Extending the structure-activity relationship of anthranilic acid derivatives as farnesoid X receptor modulators: development of a highly potent partial farnesoid X receptor agonist

J Med Chem. 2014 Oct 9;57(19):8035-55. doi: 10.1021/jm500937v. Epub 2014 Sep 25.


The ligand activated transcription factor nuclear farnesoid X receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the receptor to the full extent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Discovery
  • Hep G2 Cells
  • Humans
  • Molecular Docking Simulation
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Structure-Activity Relationship
  • ortho-Aminobenzoates / chemical synthesis*
  • ortho-Aminobenzoates / pharmacology


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