Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist.

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Kainuma M, Makishima M, Hashimoto Y, Miyachi H

Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist.

Bioorg Med Chem. 2007 Apr 1;15(7):2587-600. Epub 2007 Jan 31.

PubMed ID

17292610 [ View in PubMed

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Abstract

A series of substituted-isoxazole derivatives was prepared as candidate farnesoid X receptor (FXR) antagonists, based on our previously proposed ligand superfamily concept. Structure-activity relationship studies indicated that the shape and the structural bulkiness of the substituent at the 5-position of the isoxazole ring affected FXR-antagonistic activity. Compounds 15 g (5-substituent: 2-naphthyl) and 15 h (5-substituent: 4-biphenyl) were identified as potent antagonists with higher selectivity for FXR over progesterone receptor than the naturally occurring FXR antagonist GS. The 5-substituent is also a critical determinant of the characteristic corepressor recruitment profile of this class of FXR antagonists, though distinct mechanisms appear to be involved: 15 h stabilizes the corepressor-nuclear receptor interaction, while 15 g inhibits coactivator recruitment.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Chenodeoxycholic acid	Bile acid receptor	EC 50 (nM)	27000	7.2	37	Details