Structure-based discovery of pyrazolamides as novel ERRγ inverse agonists.

Estrogen-related receptor-gamma (ERRγ) is an orphan nuclear receptor with high structural similarity to estrogen receptors (ERα and β). The endogenous ligand of the receptor has yet to be identified. Only two classes of molecules-stilbene (diethylstilbestrol, 4-hydroxytamoxifen, and GSK5182) and flavonol (kaempferol) have been known to modulate the transcriptional activity of the receptor to date. Further, these agents lack selectivity to ERRγ suggesting the need for a new inverse agonist. Thus, virtual screening was used to identify pyrazolamide 7 as a novel ERRγ inverse agonist. Structure-based diversification and optimization of the compound further led to the identification of derivative 19 as a potent inverse agonist of ERRγ with selectivity over other nuclear receptors including those of ERR family. Pyrazolamide 19 exhibits strong affinity towards ERRγ and inhibits the expression of hepcidin, fibrinogen and gluconeogenic genes, which suggests that these compounds may have antimicrobial, anti-coagulant and antidiabetic activities.

[1]  S. Dooley,et al.  Orphan nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression , 2017, PloS one.

[2]  T. Choi,et al.  Structure-Based Discovery of Novel Cyclophilin A Inhibitors for the Treatment of Hepatitis C Virus Infections. , 2015, Journal of medicinal chemistry.

[3]  Hyung-Seok Kim,et al.  Inverse agonist of estrogen-related receptor γ controls Salmonella typhimurium infection by modulating host iron homeostasis , 2014, Nature Medicine.

[4]  S. Koo,et al.  Inverse Agonist of Nuclear Receptor ERRγ Mediates Antidiabetic Effect Through Inhibition of Hepatic Gluconeogenesis , 2013, Diabetes.

[5]  Keesook Lee,et al.  SAR based design of nicotinamides as a novel class of androgen receptor antagonists for prostate cancer. , 2013, Journal of medicinal chemistry.

[6]  Suk Hee Cho,et al.  Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist* , 2012, The Journal of Biological Chemistry.

[7]  S. Koo,et al.  Orphan Nuclear Receptor Estrogen-Related Receptor γ (ERRγ) Is Key Regulator of Hepatic Gluconeogenesis* , 2012, The Journal of Biological Chemistry.

[8]  J. Min,et al.  Estrogen-related Receptor γ (ERRγ) Is a Novel Transcriptional Regulator of Phosphatidic Acid Phosphatase, LIPIN1, and Inhibits Hepatic Insulin Signaling* , 2011, The Journal of Biological Chemistry.

[9]  F. Fang,et al.  Kaempferol is an estrogen‐related receptor α and γ inverse agonist , 2009, FEBS letters.

[10]  T. Willson,et al.  Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma. , 2006, Bioorganic & medicinal chemistry letters.

[11]  J. Vanacker,et al.  Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand. , 2003, Journal of molecular endocrinology.

[12]  D. Moras,et al.  Structure-activity relationship of nuclear receptor-ligand interactions. , 2003, Current topics in medicinal chemistry.

[13]  V. Giguère,et al.  4-Hydroxytamoxifen Is an Isoform-Specific Inhibitor of Orphan Estrogen-Receptor-Related (ERR) Nuclear Receptors β and γ. , 2001, Endocrinology.

[14]  J. Lehmann,et al.  4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[15]  A. Steinmetz,et al.  Binding of ligands and activation of transcription by nuclear receptors. , 2001, Annual review of biophysics and biomolecular structure.

[16]  J. Rossant,et al.  Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERR beta. , 2001, Genes & development.

[17]  D. J. Heard,et al.  Human ERRgamma, a third member of the estrogen receptor-related receptor (ERR) subfamily of orphan nuclear receptors: tissue-specific isoforms are expressed during development and in the adult. , 2000, Molecular endocrinology.

[18]  M. Stallcup,et al.  Hormone-independent Transcriptional Activation and Coactivator Binding by Novel Orphan Nuclear Receptor ERR3* , 1999, The Journal of Biological Chemistry.

[19]  David A. Agard,et al.  The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen , 1998, Cell.

[20]  H. King,et al.  Global Burden of Diabetes, 1995–2025: Prevalence, numerical estimates, and projections , 1998, Diabetes Care.

[21]  W. Kimberling,et al.  Isolation of a gene encoding a novel member of the nuclear receptor superfamily from the critical region of Usher syndrome type IIa at 1q41. , 1998, Genomics.