Insights of a Lead Optimization Study and Biological Evaluation of Novel 4‑Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with <b>3</b> (GSK5182). <b>6g</b> and <b>10b</b> had comparable potency to <b>3</b> and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of <b>6g</b> and <b>10b</b> were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in <b>6g</b>- or <b>10b</b>-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, <b>6g</b> and <b>10b</b> possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders