Discovery, Optimization, and Evaluation of Novel ANGPTL3 Modulators for the Treatment of Hyperlipidemia
文献类型：期刊论文
| 作者 | Zhang, Shurui1,2,3; Zhao, Jing3; Xie, Xiong3; Li, Luhan2,3; Chen, Jiayi3; Liu, Hong2,3,4; Wang, Jiang1,3 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-09-25 |
| 卷号 | 68期号:18页码:18930-18948 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.5c00732 |
| 英文摘要 | Angiopoietin-like protein 3 (ANGPTL3) has emerged as an attractive therapeutic target for treating hyperlipidemia. Evinacumab, a monoclonal antibody targeting ANGPTL3, was approved by the FDA for homozygous familial hypercholesterolemia in 2021. Here, a series of novel sulfonamide scaffold ANGPTL3 modulators were designed and synthesized based on the structure-activity relationship (SAR) analysis. Among them, compound 20 exhibited potent inhibition of ANGPTL3 gene expression with an IC50 value of 0.22 mu M, reduced both ANGPTL3 mRNA and protein levels, and significantly enhanced lipoprotein lipase (LPL) activity. More importantly, compound 20 remarkably lowered serum levels of triglycerides (TG), total cholesterol, and LDL cholesterol (LDL-C) in high-fat-diet-induced hyperlipidemic models, with favorable pharmacokinetic properties and safety profiles. Collectively, a novel ANGPTL3 small-molecule modulator compound 20 with a distinct core structure was first reported, offering potential for therapeutic development in hyperlipidemia. |
| WOS关键词 | CHOLESTEROL ; IDENTIFICATION ; HUMANIZATION ; INHIBITION |
| 资助项目 | National Natural Science Foundation of China[82322063] ; National Natural Science Foundation of China[22177124] ; National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[22337003] ; National Natural Science Foundation of China[92253305] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[LG-GG-202403-01] ; National Natural Science Foundation of China[23XD1460300] ; Program of Shanghai Academic Research Leader[23S11905100] ; Shanghai 2023 Biopharmaceutical Science and Technology Support Program |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001572351000001 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321462]  |
| 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 | Liu, Hong; Wang, Jiang |
| 作者单位 | 1.Lingang Lab, Shanghai 200000, Peoples R China 2.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Shurui,Zhao, Jing,Xie, Xiong,et al. Discovery, Optimization, and Evaluation of Novel ANGPTL3 Modulators for the Treatment of Hyperlipidemia[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(18):18930-18948. |
| APA | Zhang, Shurui.,Zhao, Jing.,Xie, Xiong.,Li, Luhan.,Chen, Jiayi.,...&Wang, Jiang.(2025).Discovery, Optimization, and Evaluation of Novel ANGPTL3 Modulators for the Treatment of Hyperlipidemia.JOURNAL OF MEDICINAL CHEMISTRY,68(18),18930-18948. |
| MLA | Zhang, Shurui,et al."Discovery, Optimization, and Evaluation of Novel ANGPTL3 Modulators for the Treatment of Hyperlipidemia".JOURNAL OF MEDICINAL CHEMISTRY 68.18(2025):18930-18948. |
入库方式： OAI收割
来源：上海药物研究所
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