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

文献类型：期刊论文

作者Li, Na1,5,6,7; Wang, Linlin3,4; Hu, Xinyuan3,4; Xu, Haiyan3; Yang, Bowen6,7; Zhan, Li3; Cai, Yongjie3; Gu, Yueling3; Chen, Xueqin3; Zheng, Yueming2,3
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-09-05
卷号293页码:24
关键词Voltage-gated sodium channel 1.8 Conformational restriction Pharmacokinetic Structure-activity relationship Analgesic
ISSN号0223-5234
DOI10.1016/j.ejmech.2025.117697
通讯作者Zheng, Yueming(zhengyueming@simm.ac.cn) ; Liu, Tongchao(tongchao_liu@simm.ac.cn) ; Gao, Zhaobing(zbgao@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn)
英文摘要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.
WOS关键词SODIUM-CHANNEL BLOCKER ; PHARMACOLOGICAL CHARACTERIZATION ; CHRONIC PAIN ; NA(V)1.8 ; OPTIMIZATION ; A-803467
资助项目National Natural Science Foundation of China[82173658] ; National Natural Science Foundation of China[81773572] ; National Natural Science Foundation of China[82204187] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB1060402] ; National Science and Technology Innovation 2030 Major Program[2021ZD0200900]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001502101000001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/318174]  
专题中国科学院上海药物研究所
通讯作者Zheng, Yueming; Liu, Tongchao; Gao, Zhaobing; Xiong, Bing
作者单位1.Lingang Lab, Shanghai 200031, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
5.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Na,Wang, Linlin,Hu, Xinyuan,et al. Conformational restriction enables discovering a series of chroman derivatives as potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,293:24.
APA Li, Na.,Wang, Linlin.,Hu, Xinyuan.,Xu, Haiyan.,Yang, Bowen.,...&Xiong, Bing.(2025).Conformational restriction enables discovering a series of chroman derivatives as potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,293,24.
MLA Li, Na,et al."Conformational restriction enables discovering a series of chroman derivatives as potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 293(2025):24.

入库方式： OAI收割

来源：上海药物研究所

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