Yang Su Hui, Khadka Daulat Bikram, Han Jinhe, Na Soon-Young, Shin Minsang, Kim Don-Kyu, Oh Byung-Chul, Kim Eun Young, Choi Hueng-Sik, Cho Won-Jea
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwang-ju, 61186, Republic of Korea.
School of Biological Sciences and Technology, Chonnam National University, Gwang-ju, 61186, Republic of Korea.
Eur J Med Chem. 2023 Mar 15;250:115174. doi: 10.1016/j.ejmech.2023.115174. Epub 2023 Feb 10.
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.
雌激素相关受体γ（ERRγ）是一种孤儿核受体，与雌激素受体（ERα和β）具有高度的结构相似性。该受体的内源性配体尚未确定。迄今为止，已知只有两类分子——二苯乙烯（己烯雌酚、4-羟基他莫昔芬和GSK5182）和黄酮醇（山奈酚）可调节该受体的转录活性。此外，这些药物对ERRγ缺乏选择性，这表明需要一种新的反向激动剂。因此，采用虚拟筛选来鉴定吡唑酰胺7作为一种新型ERRγ反向激动剂。基于结构的化合物多样化和优化进一步导致鉴定出衍生物19作为一种有效的ERRγ反向激动剂，对包括ERR家族在内的其他核受体具有选择性。吡唑酰胺19对ERRγ表现出强亲和力，并抑制铁调素、纤维蛋白原和糖异生基因的表达，这表明这些化合物可能具有抗菌、抗凝血和抗糖尿病活性。
