title: Hyodeoxycholic acid derivatives as liver X receptor α and G-protein-coupled bile acid receptor agonists.
abstract: Bile acids are extensively investigated for their potential in the treatment of human disorders. The liver X receptors (LXRs), activated by oxysterols and by a secondary bile acid named hyodeoxycholic acid (HDCA), have been found essential in the regulation of lipid homeostasis in mammals. Unfortunately, LXRα activates lipogenic enzymes causing accumulation of lipid in the liver. In addition to LXRs, HDCA has been also shown to function as ligand for GPBAR1, a G protein coupled receptor for secondary bile acids whose activation represents a promising approach to liver steatosis. In the present study, we report a library of HDCA derivatives endowed with modulatory activity on the two receptors. The lead optimization of HDCA moiety was rationally driven by the structural information on the binding site of the two targets and results from pharmacological characterization allowed the identification of hyodeoxycholane derivatives with selective agonistic activity toward LXRα and GPBAR1 and notably to the identification of the first example of potent dual LXRα/GPBAR1 agonists. The new chemical entities might hold utility in the treatment of dyslipidemic disorders.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Naples, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: De Marino
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, I-80131 Naples, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Masullo
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 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 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, I-80131 Naples, Italy.
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano, 49, I-80131 Naples, Italy.|Università della Svizzera Italiana (USI), Faculty of Informatics, Institute of Computational Science - Center for Computational Medicine in Cardiology, Via G. Buffi 13, CH-6900 Lugano, Switzerland.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Limongelli
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.
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
mesh_terms: D000818:Animals; D003840:Deoxycholic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D000071518:Liver X Receptors / Q000819:agonists* / Q000737:chemistry; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000737:chemistry
chemical_list: C473772:GPBAR1 protein, human; D000071518:Liver X Receptors; D043562:Receptors, G-Protein-Coupled; D003840:Deoxycholic Acid; C010471:hyodeoxycholic acid