Structure-based discovery of pyrazolamides as novel ERRγ inverse agonists

Abstract

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.