{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T11:02:19Z","timestamp":1770807739122,"version":"3.50.0"},"reference-count":36,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Special Funds of National Natural Science Foundation of China","award":["82441046"],"award-info":[{"award-number":["82441046"]}]},{"name":"Zhongshan Municipal Natural Science Foundation","award":["2023B2019"],"award-info":[{"award-number":["2023B2019"]}]},{"name":"Creative Research Group of Zhongshan City","award":["CXTD2022011"],"award-info":[{"award-number":["CXTD2022011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Dravet syndrome (DS) and Lennox\u2013Gastaut 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\u2013activity 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.<\/jats:p>","DOI":"10.3390\/molecules31030460","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:56:12Z","timestamp":1769615772000},"page":"460","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structure\u2013Activity Relationship Study on Soticlestat Derivatives for the Discovery of CYP46A1 (CH24H) Inhibitors"],"prefix":"10.3390","volume":"31","author":[{"given":"Xinwei","family":"Hu","sequence":"first","affiliation":[{"name":"Guangzhou University of Chinese Medicine, Guangzhou 510006, China"},{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqian","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotong","family":"Lin","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yishu","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiang","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8170-2909","authenticated-orcid":false,"given":"Guilong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Guangzhou University of Chinese Medicine, Guangzhou 510006, China"},{"name":"Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China"},{"name":"Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s10072-017-3188-y","article-title":"Lennox-Gastaut syndrome: A comprehensive review","volume":"39","year":"2018","journal-title":"Neurol. 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