title: Insights on FXR selective modulation. Speculation on bile acid chemical space in the discovery of potent and selective agonists.
abstract: Bile acids are the endogenous modulators of the nuclear receptor FXR and the membrane receptor GPBAR1. FXR represents a promising pharmacological target for the treatment of cholestatic liver disorders. Currently available semisynthetic bile acid derivatives cover the same chemical space of bile acids and therefore they are poorly selective toward BA receptors, increasing patient risk for adverse side effects. In this report, we have investigated around the structure of CDCA describing the synthesis and the in vitro and in vivo pharmacological characterization of a novel family of compounds modified on the steroidal tetracyclic core and on the side chain. Pharmacological characterization resulted in the identification of several potent and selective FXR agonists. These novel agents might add utility in the treatment of cholestatic disorders by potentially mitigating side effects linked to unwanted activation of GPBAR1.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, 80131 Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, 80131 Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Festa
authors.affiliation: Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi 1, 06132 Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.affiliation: Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi 1, 06132 Perugia, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.affiliation: Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi 1, 06132 Perugia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, 80131 Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Finamore
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, 80131 Naples, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Masullo
authors.affiliation: PhD Program in Drug Discovery and Development, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano (Salerno), Italy.|Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (Salerno), Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Del Gaudio
authors.affiliation: PhD Program in Drug Discovery and Development, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano (Salerno), Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.affiliation: Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi 1, 06132 Perugia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, 80131 Naples, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D000818:Animals; D002793:Cholic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D015533:Transcriptional Activation / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002793:Cholic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human