Lin Chao, Li Peiwu, Zhang Yixing, Wei Youyan, Zhang Qiuyan
Shandong College of Traditional Chinese Medicine, Department Traditional Chinese Medicine, Yantai, Shandong 264100, China.
Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, Shandong 264000, China.
Bioorg Chem. 2025 Sep;164:108880. doi: 10.1016/j.bioorg.2025.108880. Epub 2025 Aug 21.
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-CCl-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.
代谢功能障碍相关脂肪性肝炎（MASH）是代谢功能障碍相关脂肪性肝病（MASLD）的一个进展阶段，其特征为脂肪变性、炎症、肝细胞气球样变和纤维化。瑞美替隆是一种甲状腺激素受体β（THR-β）激动剂，是美国食品药品监督管理局（FDA）批准用于治疗MASH的首个药物。THR-β激动剂对血脂水平的有益作用主要源于其对肝脏中THR-β的作用，而包括对心脏和骨骼健康影响在内的不良反应则是通过甲状腺激素受体α（THR-α）介导的。在本研究中，我们报告了一系列肝脏靶向性磷酸化甲状腺激素受体激动剂的发现，这些激动剂融合了药效基团THR-β激动剂VK2809和瑞美替隆。进一步优化得到了化合物29a，它在高胆固醇喂养的大鼠模型中表现出显著的降胆固醇作用，并显示出良好的靶向特性，主要分布在肝脏和肾脏组织中。化合物29a具有优异的药代动力学性质和良好的安全性，在高脂饮食-四氯化碳诱导的小鼠MASH模型中显示出强大的抗MASH作用。总体而言，这些发现表明化合物29a在治疗MASH和其他炎症及纤维化疾病方面具有很大的潜力。
