title: 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.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kainuma
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010957:Plasmids; D011374:Progesterone / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D007202:Indicators and Reagents; D007555:Isoxazoles; D008024:Ligands; D011374:Progesterone; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064