Potent dual agonists of nuclear and membrane bile acid receptors

Considered for many years as the final product of cholesterol catabolism, bile acids are experiencing a new life, being recognized as key elements of endocrine functions, related to homeostasis of cholesterol levels, control of lipid and carbohydrate metabolism, regulation on immune system. Bile acids exert their 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). GP-BAR1/FXR dual agonists represent innovative strategy for the treatment of entero-endocrine disorders. In this communication, we report the design, total synthesis and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists. We elucidate also the binding mode of the most potent dual agonists in the two receptors. So this study provides the molecular bases of ligand/receptor interaction, useful for designing novel dual agonists.