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

Back door modulation of the farnesoid X receptor: design, synthesis, and biological evaluation of a series of side chain modified chenodeoxycholic acid derivatives.

J Med Chem. 2006 Jul 13;49(14):4208-15.

PubMed ID

16821780 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Chenodeoxycholic acid	Bile acid receptor	EC 50 (nM)	8660	N/A	N/A	Details