Towards FXR selectivity: manipulation of 6-ethylcholane scaffold

Bile acids, the end-products of cholesterol catabolism, are signaling molecules activating several cellular networks through the recognition of nuclear and membrane receptors, such as the farnesoid-x-receptor (FXR) and a G-proteins coupled receptor (GP-BAR1). BAs are generated in the liver as primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), conjugated with glycine and taurine, and then secreted in the small intestine and transformed by the intestinal microbiota into secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). CDCA is the endogenous agonist of FXR while LCA and its corresponding tauro- and glyco-conjugates (GLCA and TLCA) are the most potent natural agonists for GP-BAR1. The main physiological role of FXR is the regulation of bile acids absorption, synthesis and secretion in the intestine, liver and kidney and it is considered a promising target in cholestasis. Although, GP-BAR1 agonists represent a novel opportunity in the treatment of entero-hepatic and metabolic disorders, a recent study has provided evidence that this receptor is the physiologic mediator of pruritus, a common symptom observed in cholestasis. In this contest, we have manipulated the scaffold of 6-ethylcholane acid (6-ECDCA), a semi-synthetic bile acid, to obtain potent and selective FXR agonist.