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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Cells, Cultured
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DNA-Binding Proteins / agonists
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DNA-Binding Proteins / antagonists & inhibitors*
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Dose-Response Relationship, Drug
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Drug Design
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Humans
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Indicators and Reagents
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Isoxazoles / pharmacology
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Ligands
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Magnetic Resonance Spectroscopy
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Plasmids
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Progesterone / pharmacology
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Receptors, Cytoplasmic and Nuclear / agonists
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Transcription Factors / agonists
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Transcription Factors / antagonists & inhibitors*
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Transcriptional Activation / physiology
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Transfection
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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DNA-Binding Proteins
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Indicators and Reagents
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Isoxazoles
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Ligands
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Receptors, Cytoplasmic and Nuclear
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Transcription Factors
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farnesoid X-activated receptor
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Progesterone
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GW 4064