AUTHOR=Festa Carmen , De Marino Simona , Carino Adriana , Sepe Valentina , Marchianò Silvia , Cipriani Sabrina , Di Leva Francesco S. , Limongelli Vittorio , Monti Maria C. , Capolupo Angela , Distrutti Eleonora , Fiorucci Stefano , Zampella Angela TITLE=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 JOURNAL=Frontiers in Pharmacology VOLUME=8 YEAR=2017 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00162 DOI=10.3389/fphar.2017.00162 ISSN=1663-9812 ABSTRACT=

Bile acid (BA) 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 derivatives. The pharmacological characterization and molecular docking studies for the structure-activity rationalization, allowed the identification of 3β-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 PPARα, PPARγ, LXRα, and LXRβ and the membrane G-coupled BA 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, OSTα, and FGF21, while represses the expression of CYP7A1 gene that is negatively regulated by FXR. Collectively these effects result in a significant reshaping of BA pool in mouse. In summary, compound 2 represents a promising candidate for drug development in liver and metabolic disorders.