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)

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.