title: Back door modulation of the farnesoid X receptor: design, synthesis, and biological evaluation of a series of side chain modified chenodeoxycholic acid derivatives.
abstract: Carbamate derivatives of bile acids were synthesized with the aim of systematically exploring the potential for farnesoid X receptor (FXR) modulation endowed with occupancy of the receptor's back door, localized between loops H1-H2 and H4-H5. Since it was previously shown that bile acids bind to FXR by projecting the carboxylic tail opposite the transactivation function 2 (AF-2, helix 12), functionalization of the side chain is not expected to interfere directly with the orientation of H12 but can result in a more indirect way of receptor modulation. The newly synthesized compounds were extensively characterized for their ability to modulate FXR function in a variety of assays, including the cell-free fluorescence resonance energy transfer (FRET) assay and the cell-based luciferase transactivation assay, and displayed a broad range of activity from full agonism to partial antagonism. Docking studies clearly indicate that the side chain of the new derivatives fits in a so far unexploited receptor cavity localized near the "back door" of FXR. We thus demonstrate the possibility of achieving a broad FXR modulation without directly affecting the H12 orientation.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo, 1, 06123 Perugia, Italy. rp@unipg.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.forename: Bahman M
authors.initials: BM
authors.lastname: Sadeghpour
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Udo
authors.initials: U
authors.lastname: Meyer
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Parks
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena-Guadix
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
mesh_terms: D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D031541:Fluorescence Resonance Energy Transfer; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000235:genetics; D008958:Models, Molecular; D056920:Nuclear Receptor Coactivator 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid / Q000378:metabolism; D020218:Response Elements; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D008024:Ligands; D008156:Luciferases; D056920:Nuclear Receptor Coactivator 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C538859:NCOA1 protein, human