Structure-Activity Relationship Study on Soticlestat Derivatives for the Discovery of CYP46A1 (CH24H) Inhibitors
文献类型：期刊论文
| 作者 | Hu, Xinwei1,2; Huang, Wenqian2,3,4; Lin, Xiaotong2; Zhang, Hao2,3,4; Huang, Yishu2,3,4; Wu, Jiang5; Zhao, Guilong1,2,3,4 |
| 刊名 | MOLECULES
 |
| 出版日期 | 2026-01-28 |
| 卷号 | 31期号:3页码:72 |
| 关键词 | CH24H soticlestat structure-activity relationship Dravet syndrome Lennox-Gastaut syndrome |
| DOI | 10.3390/molecules31030460 |
| 通讯作者 | Wu, Jiang(wujiang@sztu.edu.cn) ; Zhao, Guilong(zhao_guilong@126.com) |
| 英文摘要 | Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare, severe developmental and epileptic encephalopathies with poor prognosis, and novel drugs are urgently needed to meet clinical needs. CYP46A1 (cholesterol 24-hydroxylase, CH24H) is mainly responsible for the metabolism of cholesterol to 24(S)-hydroxycholesterol in the brain and is implicated in many brain disorders through the mediation of excitatory amino acid transporter 2 (EAAT2) and N-methyl-D-aspartate (NMDA) receptors. Inhibition of CYP46A1 is supposed to provide a novel treatment for disorders associated with neural hyperexcitation, such as epilepsy and epileptic syndromes. Soticlestat, a potent CYP46A1 inhibitor being developed by Takeda, is indicated for LGS and DS but suffers from unsatisfactory in vivo potency in animal models and clinical trials. We designed three series of soticlestat derivatives to explore the structure-activity relationship (SAR) with the aim of finding more potent CYP46A1 inhibitors and understanding the SAR of CYP46A1 inhibitors represented by soticlestat. Eventually, three compounds with a benzenesulfonamide moiety (in subseries C-4) that serves as an isostere of OH in soticlestat were discovered with very potent CYP46A1 inhibitory activities comparable to soticlestat, and an interesting flat SAR profile was observed in some subseries. The findings in the present study provide insight into the SAR of CYP46A1 inhibitors and should be valuable for the future design of novel CYP46A1 inhibitors. |
| WOS关键词 | LENNOX-GASTAUT SYNDROME ; CHOLESTEROL ; RECEPTOR ; POTENT |
| 资助项目 | Creative Research Group of Zhongshan City (Lingnan Pharmaceutical Research and Innovation team)[CXTD2022011] ; Special Funds of National Natural Science Foundation of China[82441046] ; Zhongshan Municipal Natural Science Foundation[2023B2019] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001687974700001 |
| 出版者 | MDPI |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322975]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wu, Jiang; Zhao, Guilong |
| 作者单位 | 1.Guangzhou Univ Chinese Med, Guangzhou 510006, Peoples R China 2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Shenzhen Technol Univ, Coll Pharm, Shenzhen 518118, Peoples R China |
| 推荐引用方式 GB/T 7714 | Hu, Xinwei,Huang, Wenqian,Lin, Xiaotong,et al. Structure-Activity Relationship Study on Soticlestat Derivatives for the Discovery of CYP46A1 (CH24H) Inhibitors[J]. MOLECULES,2026,31(3):72. |
| APA | Hu, Xinwei.,Huang, Wenqian.,Lin, Xiaotong.,Zhang, Hao.,Huang, Yishu.,...&Zhao, Guilong.(2026).Structure-Activity Relationship Study on Soticlestat Derivatives for the Discovery of CYP46A1 (CH24H) Inhibitors.MOLECULES,31(3),72. |
| MLA | Hu, Xinwei,et al."Structure-Activity Relationship Study on Soticlestat Derivatives for the Discovery of CYP46A1 (CH24H) Inhibitors".MOLECULES 31.3(2026):72. |
入库方式： OAI收割
来源：上海药物研究所
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