Conformational analysis of soticlestat, an inhibitor of CYP46A1 (CH24H), and its derivatives by variable-temperature nmr and computational methods

IF 2.2 4区化学 Q3 CHEMISTRY, MULTIDISCIPLINARY

Structural Chemistry Pub Date : 2025-01-22 DOI:10.1007/s11224-025-02459-w

Wenqian Huang, Xinwei Hu, Xiaotong Lin, Maaz Khan, Chunli Qian, Jiang Wu, Fancui Meng, Guilong Zhao

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Abstract

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.

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CYP46A1 （CH24H）抑制剂soticlestat及其衍生物的变温核磁共振和计算分析

收缩异构和限制酰胺CO-N键旋转是药物发现和开发中常见的结构特征。受CYP46A1抑制剂soticlestat （S-1）异常的核磁共振谱启发，通过13C变温核磁共振、分子力学、量子力学和高效液相色谱等手段，设计、合成并研究了soticlestat及其14种结构相近的类似物，以探索影响限制键旋转和稳定构象数量的结构特征。结果表明，在室温下，索替列斯汀有4种稳定的构象，它们分别以2个非对映体的形式存在，每对对映体为一对，并且这些构象的相互转化率在核磁共振时间尺度上是中间的，但在HPLC上是不可分离的，证明索替列斯汀可以被开发为4种旋转异构体的混合物。

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来源期刊

Structural Chemistry 化学-化学综合

CiteScore

3.80

自引率

11.80%

发文量

227

审稿时长

3.7 months

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.