2. Academic Validation
  3. Conformational restriction enables discovering a series of chroman derivatives as potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties

Conformational restriction enables discovering a series of chroman derivatives as potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties

  • Eur J Med Chem. 2025 May 6:293:117697. doi: 10.1016/j.ejmech.2025.117697.
Na Li 1,  Linlin Wang 2,  Xinyuan Hu 2,  Haiyan Xu 3,  Bowen Yang 4,  Li Zhan 3,  Yongjie Cai 3,  Yueling Gu 3,  Xueqin Chen 3,  Yueming Zheng 5,  Tongchao Liu 6,  Zhaobing Gao 7,  Bing Xiong 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zhengyueming@simm.ac.cn.
  • 6 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: tongchao_liu@simm.ac.cn.
  • 7 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zbgao@simm.ac.cn.
  • 8 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: bxiong@simm.ac.cn.
PMID: 40347793 DOI: 10.1016/j.ejmech.2025.117697
Abstract

Voltage-gated Sodium Channel 1.8 (NaV1.8) is a promising analgesic target due to its unique biophysical characteristics and specific role in nociceptive sensation. VX-150 initially completed proof-of-concept studies in clinical trials, but with high dosages and frequent administration. Herein, based on VX-150, we report the design, synthesis and structure-activity relationship (SAR) study aiming to identify novel, potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties. Conformational restriction strategy and subsequent optimization led to the identification of the chroman derivative (R)-40 as the most promising hNaV1.8 inhibitor showing an IC50 value of 5.9 ± 1.0 nM and good selectivity over Other tested NaV channels and hERG channel. More importantly, (R)-40 showed good in vitro metabolic stability in liver microsomes across multiple species and excellent in vivo PK profiles in rats and dogs. Notably, (R)-40 exerted dose-dependent analgesic activities in both rat models with postoperative and inflammatory pain, and a wide safety margin in neurotoxicity evaluation. Overall, these results confirmed conformational restriction as an effective strategy to improve PK profile, and our detailed study provided a valuable foundation for developing novel NaV1.8 inhibitors.

Keywords

Analgesic; Conformational restriction; Pharmacokinetic; Structure-activity relationship; Voltage-gated sodium channel 1.8.

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