Modification of semisynthetic bile acid derivatives as human receptor modulators

Bile acids (BAs), the end products of cholesterol catabolism, are able to interact with nuclear and membrane endogenous receptors, inducing several cellular networks that regulate lipids, glucose and bile acids homeostasis. Cholic acid (CA) and chenodeoxycholic acid (CDCA) are the major primary bile acids synthesized in human livers, and are conjugated with taurine or glycine for secretion into bile. Two targets of BAs are the endogenous nuclear receptor FXR (farnesoid-X-receptor) and the membrane receptor GPBAR1 (G-protein coupled receptor 1) (1-2) and since their activation is linked to the control of different metabolic and enterohepatic functions, they could be considered efficient targets in the treatment of several human diseases (3-5). One limit of the therapeutic use of BA derivatives is their promiscuity in binding different receptors and inducing an increase of risk for adverse side effects. In addition, the carboxyl group on the side chain conjugates with taurine and glycine, and the conjugated metabolites undergo to extensive enterohepatic circulation, resulting in the risk of drug accumulation. In the last years, medicinal chemistry modifications on bile acid scaffolds, mainly performed on chenodeoxycholic acid (CDCA) and focused on the length/functionalization of the side chain, as well as on the tetracyclic core, afforded a large amount of derivatives useful in the treatment of metabolic and enterohepatic disorders, ranging from metabolic syndrome, diabetes, cholestasis and non-alcoholic steatohepatitis. In this contest, we have manipulated also the scaffold of 6-ethylcholane acid (6-ECDCA), a semi-synthetic bile acid, to obtain potent and selective FXR agonist with improved pharmacokinetic properties.