{"title":"CYP46A1 （CH24H）抑制剂soticlestat及其衍生物的变温核磁共振和计算分析","authors":"Wenqian Huang, Xinwei Hu, Xiaotong Lin, Maaz Khan, Chunli Qian, Jiang Wu, Fancui Meng, Guilong Zhao","doi":"10.1007/s11224-025-02459-w","DOIUrl":null,"url":null,"abstract":"<div><p>Atropisomerism and restricted amide CO–N bond rotation are commonly encountered structural characteristics in drug discovery and development. Inspired by the unusual NMR spectra of soticlestat (<b>S-1</b>), a CYP46A1 inhibitor currently under development in phase 3 clinical trials, soticlestat and its 14 structurally close analogs were designed, synthesized and studied by variable-temperature <sup>13</sup>C NMR, molecular mechanics, quantum mechanics and HPLC to explore the structural characteristics that affect the restricted bond rotations and the number of stable conformations. It is concluded that there are four stable conformations at room temperature which exist as two diastereomers each as a pair of enantiomers, and the interconversion rates of these conformations are intermediate on the NMR time scale but are inseparable by HPLC, justifying that soticlestat can be developed as a mixture of four rotational isomers.</p></div>","PeriodicalId":780,"journal":{"name":"Structural Chemistry","volume":"36 4","pages":"1305 - 1329"},"PeriodicalIF":2.2000,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Conformational analysis of soticlestat, an inhibitor of CYP46A1 (CH24H), and its derivatives by variable-temperature nmr and computational methods\",\"authors\":\"Wenqian Huang, Xinwei Hu, Xiaotong Lin, Maaz Khan, Chunli Qian, Jiang Wu, Fancui Meng, Guilong Zhao\",\"doi\":\"10.1007/s11224-025-02459-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Atropisomerism and restricted amide CO–N bond rotation are commonly encountered structural characteristics in drug discovery and development. Inspired by the unusual NMR spectra of soticlestat (<b>S-1</b>), a CYP46A1 inhibitor currently under development in phase 3 clinical trials, soticlestat and its 14 structurally close analogs were designed, synthesized and studied by variable-temperature <sup>13</sup>C NMR, molecular mechanics, quantum mechanics and HPLC to explore the structural characteristics that affect the restricted bond rotations and the number of stable conformations. It is concluded that there are four stable conformations at room temperature which exist as two diastereomers each as a pair of enantiomers, and the interconversion rates of these conformations are intermediate on the NMR time scale but are inseparable by HPLC, justifying that soticlestat can be developed as a mixture of four rotational isomers.</p></div>\",\"PeriodicalId\":780,\"journal\":{\"name\":\"Structural Chemistry\",\"volume\":\"36 4\",\"pages\":\"1305 - 1329\"},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2025-01-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Structural Chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s11224-025-02459-w\",\"RegionNum\":4,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Structural Chemistry","FirstCategoryId":"92","ListUrlMain":"https://link.springer.com/article/10.1007/s11224-025-02459-w","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Conformational analysis of soticlestat, an inhibitor of CYP46A1 (CH24H), and its derivatives by variable-temperature nmr and computational methods
Atropisomerism and restricted amide CO–N bond rotation are commonly encountered structural characteristics in drug discovery and development. Inspired by the unusual NMR spectra of soticlestat (S-1), a CYP46A1 inhibitor currently under development in phase 3 clinical trials, soticlestat and its 14 structurally close analogs were designed, synthesized and studied by variable-temperature 13C NMR, molecular mechanics, quantum mechanics and HPLC to explore the structural characteristics that affect the restricted bond rotations and the number of stable conformations. It is concluded that there are four stable conformations at room temperature which exist as two diastereomers each as a pair of enantiomers, and the interconversion rates of these conformations are intermediate on the NMR time scale but are inseparable by HPLC, justifying that soticlestat can be developed as a mixture of four rotational isomers.
期刊介绍：
Structural Chemistry is an international forum for the publication of peer-reviewed original research papers that cover the condensed and gaseous states of matter and involve numerous techniques for the determination of structure and energetics, their results, and the conclusions derived from these studies. The journal overcomes the unnatural separation in the current literature among the areas of structure determination, energetics, and applications, as well as builds a bridge to other chemical disciplines. Ist comprehensive coverage encompasses broad discussion of results, observation of relationships among various properties, and the description and application of structure and energy information in all domains of chemistry.
We welcome the broadest range of accounts of research in structural chemistry involving the discussion of methodologies and structures,experimental, theoretical, and computational, and their combinations. We encourage discussions of structural information collected for their chemicaland biological significance.
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