Modification on ursodeoxycholic acid (UDCA) scaffold. discovery of bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1 (GP-BAR1).

Abstract

Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3α,7β-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of pro-glucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.

• Authors: Valentina Sepe, Barbara Renga, Carmen Festa, Claudio D'Amore, Dario Masullo, Sabrina Cipriani, Francesco Saverio Di Leva, Maria Chiara Monti, Ettore Novellino, Vittorio Limongelli, Angela Zampella, Stefano Fiorucci
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 18 Pg. 7687-701 (Sep 25 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25162837 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GPBAR1 protein, human
• Receptors, G-Protein-Coupled
• Ursodeoxycholic Acid

Topics

• Drug Discovery
• HEK293 Cells
• Hep G2 Cells
• Humans
• Models, Molecular
• Protein Conformation
• Receptors, G-Protein-Coupled (agonists, chemistry)
• Substrate Specificity
• Ursodeoxycholic Acid (analogs & derivatives, pharmacology)