Discovery of UDCA derivatives as new modulators of bile acid receptors

Bile acids exert genomic and non-genomic effects by interacting with membrane G-protein coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions, thus GP-BAR1/FXR agonists, by enhancing the biological response, represent an innovative strategy for the treatment of entero-endocrine disorders. UDCA (ursodeoxycholic acid), present in human bile at low concentrations, has been shown effective in biliary and liver diseases and is now considered as the first-line treatment for primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and intrahepatic cholestasis of pr egnancy (ICP). UDCA is the 7-beta hydroxy epimer of CDCA and, despite its pharmacological profile, UDCA is not a FXR agonist and its mechanism of action remains unclear and still subjected to intense scientific debates. Indeed UDCA is considered a safety molecule with a clinical history with minimal side effects, also when used in large doses. In this context we decided to manipulate UDCA chemical scaffold obtaining a large library of derivatives. This research work resulted in the identification, for the first time, of several UDCA analogues endowed with bile acid receptors agonistic profile.