Design, synthesis, and biological evaluation of liver-targeting phosphoric acid thyroid hormone receptor agonists for the treatment of metabolic dysfunction-associated steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive stage of metabolic dysfunction-associated steatotic liver disease (MASLD) and is characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis. Resmetirom, a Thyroid Hormone Receptor β (THR-β) agonist, is the first drug approved by the FDA for the treatment of MASH. The beneficial effects of THR-β agonists on lipid levels primarily result from their action on THR-β in the liver, whereas adverse effects, including impacts on cardiac and bone health, are mediated through Thyroid Hormone Receptor α (THR-α). In this study, we report the discovery of a series of liver-targeting phosphoric acid Thyroid Hormone Receptor agonists that merge the pharmacophores THR-β agonists VK2809 and resmetirom. Further optimization led to compound 29a, which exhibited significant cholesterol-lowering effects in a cholesterol-fed rat model and demonstrated favorable targeting properties, with primary distribution in liver and kidney tissues. Compound 29a, which had excellent PK properties and a good safety profile, showed potent anti-MASH effects in HFD-CCl₄-induced mice MASH model. Collectively, these findings suggest that compound 29a holds considerable promise for the treatment of MASH and Other inflammatory and fibrotic diseases.