Targeting bile acid receptors: discovery of a potent and selective Farnesoid X receptor agonist as a new lead in the pharmacological approach to liver diseases

Bile acid receptors represent well-defined targets for the development of novel therapeutic approaches to metabolic and inflammatory diseases. In the present study, we report the generation of novel C-3 modified 6-ethylcholane. The pharmacological characterization and molecular docking studies for the structure-activity rationalization, allowed the identification of 3-azido-6α-ethyl-7α-hydroxy-5β-cholan-24-oic acid (compound 2), a potent and selective FXR agonist with a nanomolar potency in transactivation assay and high efficacy in the recruitment of SRC-1 co-activator peptide in Alfa Screen assay. In vitro, compound 2 was completely inactive towards common off-targets such as the nuclear receptors PPAR, PPAR, LXR, and LXRand the membrane G-coupled bile acid receptor, GPBAR1. This compound when administered in vivo exerts a robust FXR agonistic activity increasing the liver expression of FXR-target genes including SHP, BSEP, OST and FgF21, while represses the expression of genes that are negatively regulated by FXR (CYP7A1), and collectively these effects result in a significant reshaping of bile acid pool in mouse. In summary, compound 2 could represent a promising candidate for drug development in liver metabolic disorders.