Identification of diaryl ether-based ligands for estrogen-related receptor alpha as potential antidiabetic agents.

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Patch RJ, Searle LL, Kim AJ, De D, Zhu X, Askari HB, O'Neill JC, Abad MC, Rentzeperis D, Liu J, Kemmerer M, Lin L, Kasturi J, Geisler JG, Lenhard JM, Player MR, Gaul MD

Identification of diaryl ether-based ligands for estrogen-related receptor alpha as potential antidiabetic agents.

J Med Chem. 2011 Feb 10;54(3):788-808. doi: 10.1021/jm101063h. Epub 2011 Jan 10.

PubMed ID
21218783 [ View in PubMed
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Abstract

Estrogen-related receptor alpha (ERRalpha) 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 (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 muM). A cocrystal structure of the ligand-binding domain of ERRalpha 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 ERRalpha ligand in metabolic animal models.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
1-CYCLOHEXYL-N-{[1-(4-METHYLPHENYL)-1H-INDOL-3-YL]METHYL}METHANAMINESteroid hormone receptor ERR1IC 50 (nM)190N/AN/ADetails
BexaroteneRetinoic acid receptor RXR-alphaEC 50 (nM)2.7N/AN/ADetails
EstradiolEstrogen receptor alphaEC 50 (nM)10N/AN/ADetails
EstradiolEstrogen receptor betaEC 50 (nM)1.4N/AN/ADetails
RosiglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)350N/AN/ADetails
TO-901317Oxysterols receptor LXR-alphaEC 50 (nM)3.2N/AN/ADetails