Structure-based discovery of pyrazolamides as novel ERR? inverse agonists

Estrogen-related receptor-gamma (ERR gamma) is an orphan nuclear receptor with high structural similarity to estrogen receptors (ER alpha and 8). 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 ERR gamma suggesting the need for a new inverse agonist. Thus, virtual screening was used to identify pyrazolamide 7 as a novel ERR gamma inverse agonist. Structure-based diversification and optimization of the compound further led to the identification of derivative 19 as a potent inverse agonist of ERR gamma with selectivity over other nuclear receptors including those of ERR family. Pyrazolamide 19 exhibits strong affinity towards ERR gamma and inhibits the expression of hepcidin, fibrinogen and gluconeogenic genes, which suggests that these compounds may have antimicrobial, anti-coagulant and antidiabetic activities.

Automated summary

ERR gamma is an orphan nuclear receptor similar to estrogen receptors, but its endogenous ligand is unknown. Only stilbene and flavonol molecules have been found to modulate its transcriptional activity, but without selectivity. Therefore, virtual screening identified a novel ERR gamma inverse agonist, pyrazolamide 7, and its optimized derivative, pyrazolamide 19, showed potent and selective inverse agonistic activity towards ERR gamma. Pyrazolamide 19 exhibited strong affinity towards ERR gamma and inhibited the expression of hepcidin, fibrinogen, and gluconeogenic genes, suggesting potential antimicrobial, anti-coagulant, and antidiabetic activities.