当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Back door modulation of the farnesoid X receptor: design, synthesis, and biological evaluation of a series of side chain modified chenodeoxycholic acid derivatives.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Pellicciari R,Gioiello A,Costantino G,Sadeghpour BM,Rizzo G,Meyer U,Parks DJ,Entrena-Guadix A,Fiorucci S

doi

10.1021/jm060294k

subject

Has Abstract

pub_date

2006-07-13 00:00:00

pages

4208-15

issue

14

eissn

0022-2623

issn

1520-4804

journal_volume

49

pub_type

杂志文章

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