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

  • J Med Chem. 2025 Aug 28;68(16):17457-17472. doi: 10.1021/acs.jmedchem.5c00994.
Ju Liang  1  2  3 ,  Yipei Gu  2 ,  Liuyu Hu  2 ,  Hui Qu  2 ,  Nana Li  1  2  3 ,  Chaoyue Xia  2  3 ,  Lei Feng  2 ,  Li Qin  2 ,  Li Hai  1  3 ,  Yaxi Yang  1  2  4  3 ,  Ying Leng  2 ,  Bing Zhou  1  2  4  3
Affiliations
  • 1. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, P. R. China.
  • 4. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
PMID: 40762270 DOI: 10.1021/acs.jmedchem.5c00994
Abstract

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.

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