Identification of Diaryl Ether-Based Ligands for Estrogen-Related Receptor 伪 as Potential Antidiabetic Agents

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• 作者：Raymond J. Patch ; Lily L. Searle ; Alexander J. Kim ; Debyendu De ; Xizhen Zhu ; Hossein B. Askari ; John C. O鈥橬eill ; Marta C. Abad ; Dionisios Rentzeperis ; Jianying Liu ; Michael Kemmerer ; Ling Lin ; Jyotsna Kasturi ; John G. Geisler ; James M. Lenhard ; Mark R. Player ; Micheal D. Gaul
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 10, 2011
• 年：2011
• 卷：54
• 期：3
• 页码：788-808
• 全文大小：1236K
• 年卷期：v.54,no.3(February 10, 2011)
• ISSN：1520-4804

文摘

Estrogen-related receptor 伪 (ERR伪) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC₅₀ < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC₅₀ = 1鈭? 渭M). A cocrystal structure of the ligand-binding domain of ERR伪 with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERR伪 ligand in metabolic animal models.