title: Investigation on bile acid receptor regulators. Discovery of cholanoic acid derivatives with dual G-protein coupled bile acid receptor 1 (GPBAR1) antagonistic and farnesoid X receptor (FXR) modulatory activity.
abstract: Bile acids, the end products of cholesterol metabolism, activate multiple mechanisms through the interaction with membrane G-protein coupled receptors including the bile acid receptor GPBAR1 and nuclear receptors such as the bile acid sensor, farnesoid X receptor (FXR). Even if dual FXR/GPBAR1 agonists are largely considered a novel opportunity in the treatment of several liver and metabolic diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation is associated to severe side effects. In the present study we have investigated around the structure of LCA generating a small library of cholane derivatives, endowed with dual FXR agonism/GPBAR1 antagonism. To the best of our knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
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 Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Naples, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Festa
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-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, I-80131 Naples, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Masullo
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: Hospital S. Maria della Misericordia, S. Andrea delle Fratte, 06126 Perugia, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
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, I-80131 Naples, Italy. Electronic address: angela.zampella@unina.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D002793:Cholic Acids / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002793:Cholic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human; C007036:cholanic acid
keywords: Bile acids; FXR modulators; Farnesoid X receptor; G protein-coupled bile acid receptor; GPBAR1 antagonists