Discovery of Highly Potent, Selective, and Liver-Targeted THR‑β Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis

With the improvement of living standards, metabolic-disorder-associated steatohepatitis (MASH) has posed a serious threat to public health. In 2024, THR-β agonist Resmetirom was approved by the FDA as the first market drug for the treatment of MASH. In this work, we discovered a new class of THR-β agonists through structure-based rational design. Compound 12 exhibited much higher agonistic activity (EC50 = 11.0 nM) and higher selectivity for THR-β over THR-α (THR-β/α = 34.1) compared to the market drug Resmetirom. More importantly, good pharmacokinetic properties of 12 was observed with an excellent liver to heart ratio of 335:1. Notably, compound 12 exhibited superior ability to improve steatosis, ballooning, inflammation and fibrosis, while Resmetirom did not show any improvement in inflammation, suggesting that 12 is a highly promising THR-β agonist and warrants extensive preclinical investigation as a potential clinical development candidate for the treatment of MASH.