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 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far
more selective for ERRγ over the ERRα, -β, and ERα.
The in vivo pharmacokinetic profiles of 6g and 10b 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 6g- or 10b-treated CAL62 cells, which
indicated that these compounds could be promising enhancers for restoring
NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used
to potentially treat various ERRγ-related disorders.