Discovery of Highly Potent and Selective Thyroid Hormone Receptor βAgonists for the Treatment of Nonalcoholic Steatohepatitis
文献类型：期刊论文
| 作者 | Hu, Liuyu4,5; Gu, Yipei5; Liang, Ju1,4; Ning, Mengmeng5 ; Yang, Junli1,5; Zhang, Yi4; Qu, Hui5; Yang, Yaxi4,5; Leng, Ying3,4; Zhou, Bing1,2,4,5
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2023-03-09 |
| 卷号 | 66期号:5页码:3284-3300 |
| DOI | 10.1021/acs.jmedchem.2c01669 |
| 文献子类 | Article |
| 英文摘要 | Nonalcoholic steatohepatitis (NASH) is a progressive stage of nonalcoholic fatty liver disease (NAFLD) and is characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis. While there are currently no approved therapies for NASH, the thyroid hormone receptor beta (THR-beta), primarily expressed in the liver, is emerging as an effective molecular target for the treatment of NASH. However, the adverse cardiac and bone effects mediated by thyroid hormone receptor alpha (THR-alpha) need to be minimized. Herein, we reported the discovery of a series of novel THR-beta agonists featuring pyrrolo[3,2-b]pyridin-5-one skeletons based on structure-based drug design. Further optimization led to compound 15, which exhibited higher potency and selectivity for THR-beta over THR-alpha compared to clinical drug MGL-3196. More significantly, an excellent liver-to-serum ratio of 93:1 was observed for compound 15. We believe that the high hepatic concentration of compound 15 may result in no cardiotoxicity. |
| WOS关键词 | ACID ; CHOLESTEROL ; SERIES ; HEART ; LIGAND |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000935756300001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309699]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yang, Yaxi; Leng, Ying; Zhou, Bing |
| 作者单位 | 1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Hu, Liuyu,Gu, Yipei,Liang, Ju,et al. Discovery of Highly Potent and Selective Thyroid Hormone Receptor βAgonists for the Treatment of Nonalcoholic Steatohepatitis[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(5):3284-3300. |
| APA | Hu, Liuyu.,Gu, Yipei.,Liang, Ju.,Ning, Mengmeng.,Yang, Junli.,...&Zhou, Bing.(2023).Discovery of Highly Potent and Selective Thyroid Hormone Receptor βAgonists for the Treatment of Nonalcoholic Steatohepatitis.JOURNAL OF MEDICINAL CHEMISTRY,66(5),3284-3300. |
| MLA | Hu, Liuyu,et al."Discovery of Highly Potent and Selective Thyroid Hormone Receptor βAgonists for the Treatment of Nonalcoholic Steatohepatitis".JOURNAL OF MEDICINAL CHEMISTRY 66.5(2023):3284-3300. |
入库方式： OAI收割
来源：上海药物研究所
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