Design, Synthesis, and BiologicalEvaluation of PotentDual Agonists of Nuclear and Membrane Bile Acid Receptors.

Bileacids exert genomic and nongenomic effects by interactingwith membrane G-protein-coupled receptors, including the bile acidreceptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor(FXR). These receptors regulate overlapping metabolic functions; thus,GP-BAR1/FXR dual agonists, by enhancing the biological response, representan innovative strategy for the treatment of enteroendocrine disorders.Here, we report the design, total synthesis, and in vitro/in vivopharmacological evaluation of a new generation of dual bile acidreceptor agonists, with the most potent compound, 19,showing promising pharmacological profiles. We show that compound 19activates GP-BAR1, FXR, and FXR regulated genes in theliver, increases the intracellular concentration of cAMP, and stimulatesthe release of the potent insulinotropic hormone GLP-1, resultingin a promising drug candidate for the treatment of metabolic disorders.We also elucidate the binding mode of the most potent dual agonistsin the two receptors through a series of computations providing themolecular basis for dual GP-BAR1/FXR agonism. [ABSTRACT FROM AUTHOR]