Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist
| Autor: | Hiroyuki Miyachi, Masahiko Kainuma, Yuichi Hashimoto, Makoto Makishima |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Transcriptional Activation
Magnetic Resonance Spectroscopy Stereochemistry Clinical Biochemistry Pharmaceutical Science Receptors Cytoplasmic and Nuclear Ligands Transfection Biochemistry chemistry.chemical_compound Drug Discovery Progesterone receptor Coactivator Humans Isoxazole Molecular Biology Cells Cultured Progesterone Dose-Response Relationship Drug Organic Chemistry Anti-Inflammatory Agents Non-Steroidal Antagonist Isoxazoles Ligand (biochemistry) DNA-Binding Proteins Design synthesis chemistry Drug Design Molecular Medicine Farnesoid X receptor Indicators and Reagents Corepressor Plasmids Transcription Factors |
| Zdroj: | Bioorganicmedicinal chemistry. 15(7) |
| ISSN: | 0968-0896 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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