Identification of Selective ERRγ Inverse Agonists

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Jina KimSung Jin Cho

Abstract

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.

References

Jul 12, 2001·Proceedings of the National Academy of Sciences of the United States of America·P CowardJ M Lehmann
Nov 26, 2005·Bioorganic & Medicinal Chemistry Letters·Esther Y H ChaoWilliam J Zuercher
Mar 7, 2006·Current Topics in Medicinal Chemistry·Eric A Ariazi, V Craig Jordan
Jun 23, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Chuang LuLiang-Shang Gan
Jan 5, 2008·Nuclear Receptor Signaling·Annie M Tremblay, Vincent Giguère
May 13, 2008·Assay and Drug Development Technologies·David R PiperStephen D Hess
Jan 11, 2012·Journal of the American Chemical Society·Yuta FujiwaraPhil S Baran
May 3, 2012·The Journal of Biological Chemistry·Don-Kyu KimHueng-Sik Choi
Sep 5, 2015·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Thoudam Debraj SinghYoung Hyun Jeon

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Citations

Jul 30, 2019·Pharmaceutical Patent Analyst·Hermann Am Mucke
Apr 24, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Thoudam Debraj SinghYong Hyun Jeon
Apr 4, 2021·Antioxidants·Charlotte Scholtes, Vincent Giguère
Oct 3, 2018·Journal of Medicinal Chemistry·Joel M SmithPhil S Baran

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Methods Mentioned

BETA
column chromatography
X-ray
NMR
Assay
transfection

Software Mentioned

PyMol
Prism
Bruker Topspin
Glide
Schrödinger

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