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rdf:type |
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lifeskim:mentions |
umls-concept:C0008024,
umls-concept:C0205349,
umls-concept:C0205460,
umls-concept:C0205549,
umls-concept:C0220781,
umls-concept:C0220825,
umls-concept:C0243072,
umls-concept:C0337112,
umls-concept:C0557698,
umls-concept:C1421546,
umls-concept:C1524075,
umls-concept:C1707689,
umls-concept:C1709059,
umls-concept:C1883254
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pubmed:issue |
14
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pubmed:dateCreated |
2006-7-6
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Chenodeoxycholic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Histone Acetyltransferases,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/NCOA1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Receptor Coactivator 1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Steroid,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/farnesoid X-activated receptor
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
13
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4208-15
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:16821780-Cell Line, Tumor,
pubmed-meshheading:16821780-Chenodeoxycholic Acid,
pubmed-meshheading:16821780-DNA-Binding Proteins,
pubmed-meshheading:16821780-Drug Design,
pubmed-meshheading:16821780-Fluorescence Resonance Energy Transfer,
pubmed-meshheading:16821780-Genes, Reporter,
pubmed-meshheading:16821780-Histone Acetyltransferases,
pubmed-meshheading:16821780-Humans,
pubmed-meshheading:16821780-Ligands,
pubmed-meshheading:16821780-Luciferases,
pubmed-meshheading:16821780-Models, Molecular,
pubmed-meshheading:16821780-Nuclear Receptor Coactivator 1,
pubmed-meshheading:16821780-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:16821780-Receptors, Steroid,
pubmed-meshheading:16821780-Response Elements,
pubmed-meshheading:16821780-Structure-Activity Relationship,
pubmed-meshheading:16821780-Transcription Factors,
pubmed-meshheading:16821780-Transfection
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pubmed:year |
2006
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pubmed:articleTitle |
Back door modulation of the farnesoid X receptor: design, synthesis, and biological evaluation of a series of side chain modified chenodeoxycholic acid derivatives.
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pubmed:affiliation |
Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo, 1, 06123 Perugia, Italy. rp@unipg.it
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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