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J Med Chem. 2007 Dec 27;50(26):6722-4. Epub 2007 Dec 4.

On the intractability of estrogen-related receptor alpha as a target for activation by small molecules.

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  • 1Molecular Discovery Research Branch, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.


The estrogen-related receptor alpha (ERRalpha) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRalpha have been identified despite several high-throughput screening campaigns. We describe the synthesis and profiling of a small array of compounds designed on the basis of a previously reported agonist-bound crystal structure of the closely related receptor ERRgamma. The results suggest that ERRalpha may be intractable as a direct target for pharmacologic activation.

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