SAR studies on FXR modulators led to the discovery of the first combined FXR antagonistic/TGR5 agonistic compound

Future Med Chem. 2016;8(2):133-48. doi: 10.4155/fmc.15.178. Epub 2016 Jan 29.

Abstract

Background: Bile acids can serve as signaling molecules by activating the nuclear receptor FXR and the G-protein-coupled receptor TGR5 and both bile acid receptors are prominent experimental drug targets. Results/methodology: In this study we optimized the fatty acid mimetic compound pirinixic acid to a new scaffold with the aim to develop novel FXR modulatory compounds. After a multistep structure-activity optimization process, we discovered FXR agonistic compounds and the first dual FXR antagonistic and TGR5 agonistic compound 79a.

Conclusion: With this novel dual activity profile on both bile acid receptors 79a might be a valuable pharmalogical tool to further study the bile acid signaling network.

Keywords: FXR antagonist; bile acid receptor modulator; bile acid signaling; farnesoid X receptor; metabolic disorders; non-alcoholic steatohepatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzoic Acid / chemistry
  • Benzoic Acid / pharmacology
  • Bile Acids and Salts / chemistry*
  • Bile Acids and Salts / pharmacology
  • Cell Line, Tumor
  • HeLa Cells
  • Humans
  • Protein Binding
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship
  • Transcriptional Activation / drug effects

Substances

  • Bile Acids and Salts
  • GPBAR1 protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, G-Protein-Coupled
  • farnesoid X-activated receptor
  • Benzoic Acid