THR-β agonist 9 is a potent and selective THR-β activator, which shows sensitivity to His435 mutations with an EC50 of 3.2 nM. It demonstrates moderate selectivity, approximately 10-fold, and effectively activates various His435 mutants (H435A, H435Y, and H435R), with EC50 values ranging from 134.2 nM to 515.5 nM. THR-β agonist 9 presents potential for research into conditions such as dyslipidemia, metabolic syndrome-associated steatohepatitis (MASH), and resistance to thyroid hormone (RTH).

THR-β agonist 9 (Compound 15n) at a concentration of 1 μM activates THR-β with an EC50 of 258.2 nM while showing an activation potency of 1707.0 nM for THR-α, demonstrating remarkable selectivity in cell-based reporter gene assays. It also activates three THR-β mutants with EC50 values of 515.5 nM for THR-β H435A, 134.2 nM for THR-β H435R, and 513.1 nM for THR-β H435Y. Administered at 1-10 μM for 24 hours, it reduces triglyceride (TG) and total cholesterol (TC) levels in primary mouse hepatocytes and HepG2 cells, thus decreasing lipid accumulation. Additionally, it enhances both basal and uncoupled mitochondrial respiration in HepG2 cells. Moreover, within the same concentration and duration, THR-β agonist 9 increases the phosphorylation of AMPK and ACC, accompanied by elevated CPT1 protein levels, thereby improving metabolism in HepG2 cells via the AMPK pathway.