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Identification of Selective ERRγ Inverse Agonists

New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea
Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Korea
Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu 41944, Korea
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, Korea
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Molecules 2016, 21(1), 80;
Received: 26 November 2015 / Revised: 5 January 2016 / Accepted: 7 January 2016 / Published: 12 January 2016
(This article belongs to the Section Medicinal Chemistry)
PDF [2896 KB, uploaded 12 January 2016]


GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases. View Full-Text
Keywords: estrogen-related receptor gamma; inverse agonist; ADMET; GSK5182 estrogen-related receptor gamma; inverse agonist; ADMET; GSK5182

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kim, J.; Im, C.Y.; Yoo, E.K.; Ma, M.J.; Kim, S.-B.; Hong, E.; Chin, J.; Hwang, H.; Lee, S.; Kim, N.D.; Jeon, J.-H.; Lee, I.-K.; Jeon, Y.H.; Choi, H.-S.; Kim, S.H.; Cho, S.J. Identification of Selective ERRγ Inverse Agonists. Molecules 2016, 21, 80.

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