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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Kainuma M,Makishima M,Hashimoto Y,Miyachi H

doi

10.1016/j.bmc.2007.01.046

subject

Has Abstract

pub_date

2007-04-01 00:00:00

pages

2587-600

issue

7

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(07)00074-0

journal_volume

15

pub_type

杂志文章

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