Liang Ju, Gu Yipei, Hu Liuyu, Qu Hui, Li Nana, Xia Chaoyue, Feng Lei, Qin Li, Hai Li, Yang Yaxi, Leng Ying, Zhou Bing
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
J Med Chem. 2025 Aug 28;68(16):17457-17472. doi: 10.1021/acs.jmedchem.5c00994. Epub 2025 Aug 5.
With the improvement of living standards, metabolic-disorder-associated steatohepatitis (MASH) has posed a serious threat to public health. In 2024, THR-β agonist 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 exhibited much higher agonistic activity (EC = 11.0 nM) and higher selectivity for THR-β over THR-α (THR-β/α = 34.1) compared to the market drug . More importantly, good pharmacokinetic properties of was observed with an excellent liver to heart ratio of 335:1. Notably, compound exhibited superior ability to improve steatosis, ballooning, inflammation and fibrosis, while did not show any improvement in inflammation, suggesting that is a highly promising THR-β agonist and warrants extensive preclinical investigation as a potential clinical development candidate for the treatment of MASH.
随着生活水平的提高，代谢紊乱相关脂肪性肝炎（MASH）对公众健康构成了严重威胁。2024年，THR-β激动剂被美国食品药品监督管理局（FDA）批准为首个用于治疗MASH的上市药物。在这项工作中，我们通过基于结构的合理设计发现了一类新型的THR-β激动剂。与市售药物相比，化合物表现出更高的激动活性（EC = 11.0 nM）以及对THR-β相对于THR-α更高的选择性（THR-β/α = 34.1）。更重要的是，观察到化合物具有良好的药代动力学性质，肝心比极佳，为335:1。值得注意的是，化合物在改善脂肪变性、气球样变、炎症和纤维化方面表现出卓越的能力，而在炎症方面没有显示出任何改善，这表明化合物是一种极具潜力的THR-β激动剂，作为治疗MASH的潜在临床开发候选药物值得进行广泛的临床前研究。
