title: Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands.
abstract: Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and therefore the discovery of selective GPBAR1 and FXR agonists is an essential step in the medicinal chemistry optimization of bile acid scaffold. In this study, a new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPBAR1 were assayed. This speculation resulted in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity.
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: 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 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 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 Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, 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: Michele
authors.initials: M
authors.lastname: Biagioli
authors.affiliation: Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi 1, 06132 Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marchianò
authors.affiliation: Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano (Salerno), Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Capolupo
authors.affiliation: Department of Pharmacy, 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: D001647:Bile Acids and Salts / Q000138:chemical synthesis* / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000138:chemical synthesis* / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D015394:Molecular Structure; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D005765:Gastrointestinal Agents; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human