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<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>

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

  • 期刊论文

  • 发表日期：

    2025年1月22日

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

摘要

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.