title: Exploitation of cholane scaffold for the discovery of potent and selective farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1 (GP-BAR1) ligands.
abstract: Nuclear and G-protein coupled receptors are considered major targets for drug discovery. FXR and GP-BAR1, two bile acid-activated receptors, have gained increasing consideration as druggable receptors. Because endogenous bile acids often target both receptor families, the development of selective ligands has been proven difficult, exposing patients to side effects linked to an unwanted activation of one of the two receptors. In the present study, we describe a novel library of semisynthetic bile acid derivatives obtained by modifications on the cholane scaffold. The pharmacological characterization of this library led to the discovery of 7α-hydroxy-5β-cholan-24-sulfate (7), 6β-ethyl-3α,7β-dihydroxy-5β-cholan-24-ol (EUDCOH, 26), and 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (NorECDCOH, 30) as novel ligands for FXR and GP-BAR1 that might hold utility in the treatment of FXR and GP-BAR1 mediated disorders.
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.forename: Barbara
authors.initials: B
authors.lastname: Renga
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Amore
authors.forename: Valentina
authors.initials: V
authors.lastname: Sepe
authors.forename: Claudia
authors.initials: C
authors.lastname: Finamore
authors.forename: Simona
authors.initials: S
authors.lastname: De Marino
authors.forename: Adriana
authors.initials: A
authors.lastname: Carino
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cipriani
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Monti
authors.forename: Angela
authors.initials: A
authors.lastname: Zampella
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D002757:Cholanes / Q000737:chemistry*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057809:HEK293 Cells / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D011537:Pruritus / Q000188:drug therapy; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002757:Cholanes; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human; C513561:Gpbar1 protein, mouse