کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1356939 | 981177 | 2007 | 14 صفحه PDF | دانلود رایگان |

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.
A series of substituted-isoxazole derivatives was prepared as candidate farnesoid X receptor (FXR) antagonists, based on our previously proposed ligand superfamily concept.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 15, Issue 7, 1 April 2007, Pages 2587–2600