期刊
ENDOCRINOLOGY
卷 143, 期 2, 页码 517-524出版社
ENDOCRINE SOC
DOI: 10.1210/en.143.2.517
关键词
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资金
- NIDDK NIH HHS [DK-51281, DK-41842] Funding Source: Medline
Antagonists have been developed for several nuclear receptors but not for others, including TRs. TR antagonists may have significant clinical utility for treating hormone excess states and other conditions. A structure derived extension hypothesis was applied to synthesize a TR antagonist. The principal design feature was to attach an extension group to a TR agonist whose structure would perturb formation of the TR coactivator-binding surface. The compound, 3,5-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid, has no (TRalpha) or very weak partial (TRbeta) TR agonist activity and blocks TR binding of T-3, formation of the coactivator-binding surface, and both a positive T-3 response on a thyroid hormone response element and a negative T-3 response on the TSHbeta promoter in cultured cells. The results suggest that 3,5-dibromo-4-(3',5'-diisopropyl-4'-hydroxyphenoxy)benzoic acid is a TR antagonist for thyroid hormone response element-mediated responses, this approach can be used more generally to generate nuclear receptor antagonists, and this compound or analogues may have medical and research utility.
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