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

Masahiko Kainuma, Makoto Makishima, Yuichi Hashimoto, Hiroyuki Miyachi

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


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 15g (5-substituent: 2-naphthyl) and 15h (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: 15h stabilizes the corepressor-nuclear receptor interaction, while 15g inhibits coactivator recruitment.

Original languageEnglish
Pages (from-to)2587-2600
Number of pages14
JournalBioorganic and Medicinal Chemistry
Issue number7
Publication statusPublished - Apr 1 2007
Externally publishedYes


  • Corepressor
  • FXR
  • FXR antagonist
  • Farnesoid X receptor
  • Non-steroidal

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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