Discovery of Highly Potent, Selective, and Liver-Targeted THR-β Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis
文献类型：期刊论文
| 作者 | Liang, Ju1,2,3; Gu, Yipei2; Hu, Liuyu2; Qu, Hui2; Li, Nana1,2,3; Xia, Chaoyue2,3; Feng, Lei2; Qin, Li2; Hai, Li1,3; Yang, Yaxi1,2,3,4 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-08-28 |
| 卷号 | 68期号:16页码:17457-17472 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5c00994 |
| 英文摘要 | With the improvement of living standards, metabolic-disorder-associated steatohepatitis (MASH) has posed a serious threat to public health. In 2024, THR-beta 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-beta agonists through structure-based rational design. Compound 12 exhibited much higher agonistic activity (EC50 = 11.0 nM) and higher selectivity for THR-beta over THR-alpha (THR-beta/alpha = 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-beta agonist and warrants extensive preclinical investigation as a potential clinical development candidate for the treatment of MASH. |
| WOS关键词 | DISEASE ; CHOLESTEROL ; ACTIVATION ; GC-1 |
| 资助项目 | Key Technology Research and Development Program of Shandong Province[2024CXPT028] ; Key R&D Program of Shandong Province, China[82473755] ; National Natural Science Foundation of China[22XD1424600] ; Science and Technology Commission of Shanghai Municipality[SYS202205] ; Shanghai Municipal Science and Technology Major Project, Shandong Laboratory Program[tsqn202306322] ; Taishan Scholars Program[ZR2023JQ028] ; Taishan Scholars Program[ZR2023LSW003] ; Shandong Provincial Natural Science Foundation |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001544534300001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321213]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Yang, Yaxi; Leng, Ying; Zhou, Bing |
| 作者单位 | 1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liang, Ju,Gu, Yipei,Hu, Liuyu,et al. Discovery of Highly Potent, Selective, and Liver-Targeted THR-β Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(16):17457-17472. |
| APA | Liang, Ju.,Gu, Yipei.,Hu, Liuyu.,Qu, Hui.,Li, Nana.,...&Zhou, Bing.(2025).Discovery of Highly Potent, Selective, and Liver-Targeted THR-β Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis.JOURNAL OF MEDICINAL CHEMISTRY,68(16),17457-17472. |
| MLA | Liang, Ju,et al."Discovery of Highly Potent, Selective, and Liver-Targeted THR-β Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis".JOURNAL OF MEDICINAL CHEMISTRY 68.16(2025):17457-17472. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。