title: Design, synthesis, and biological evaluation of potent dual agonists of nuclear and membrane bile acid receptors.
abstract: Bile acids exert genomic and nongenomic 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 dual agonists, by enhancing the biological response, represent an innovative strategy for the treatment of enteroendocrine disorders. Here, we report the design, total synthesis, and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists, with the most potent compound, 19, showing promising pharmacological profiles. We show that compound 19 activates GP-BAR1, FXR, and FXR regulated genes in the liver, increases the intracellular concentration of cAMP, and stimulates the release of the potent insulinotropic hormone GLP-1, resulting in a promising drug candidate for the treatment of metabolic disorders. We also elucidate the binding mode of the most potent dual agonists in the two receptors through a series of computations providing the molecular basis for dual GP-BAR1/FXR agonism.
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia , Via Morego, 30, 16163 Genoa, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Chiara
authors.initials: C
authors.lastname: Del Gaudio
authors.forename: Maria Valeria
authors.initials: MV
authors.lastname: D'Auria
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
mesh_terms: D002757:Cholanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002757:Cholanes; D007004:Hypoglycemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human