Discovery of selective NaV1.8 inhibitors based on 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain

Hui Qin; Aihuan Wei; Yunqi Wang; Linlin Wang; Haiyan Xu; Yan Zhan; Xuechen Tian; Yueming Zheng; Zhaobing Gao; Youhong Hu

doi:10.1016/j.ejmech.2023.115371

Discovery of selective Na_V1.8 inhibitors based on 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain

Eur J Med Chem. 2023 Jun 5:254:115371. doi: 10.1016/j.ejmech.2023.115371. Epub 2023 Apr 15.

Authors

Hui Qin¹, Aihuan Wei², Yunqi Wang³, Linlin Wang³, Haiyan Xu⁴, Yan Zhan⁵, Xuechen Tian², Yueming Zheng⁶, Zhaobing Gao⁷, Youhong Hu⁸

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100039, China.
² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
³ 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.
⁴ Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
⁵ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100039, China; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: zhengyueming@simm.ac.cn.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100039, China; 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. Electronic address: zbgao@simm.ac.cn.
⁸ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100039, China. Electronic address: yhhu@simm.ac.cn.

PMID: 37084597
DOI: 10.1016/j.ejmech.2023.115371

Abstract

The Na_V1.8 channel is a genetically validated target for pain and it is mostly expressed in the peripheral nervous system. Based on the disclosed structures of Na_V1.8-selective inhibitors, we designed and synthesized a series of compounds by introducing bicyclic aromatic fragments based on the nicotinamide scaffold. In this research, a systematic structure-activity relationship study was carried out. While compound 2c possessed moderate inhibitory activity (IC₅₀ = 50.18 ± 0.04 nM) in HEK293 cells stably expressing human Na_V1.8 channels, it showed potent inhibitory activity in DRG neurons and isoform selectivity (>200-fold against human Na_V1.1, Na_V1.5 and Na_V1.7 channels). Moreover, the analgesic potency of compound 2c was identified in a post-surgical mouse model. These data demonstrate that compound 2c can be further evaluated as a non-addictive analgesic agent with reduced cardiac liabilities.

Keywords: Bicyclic aromatic groups; Na(V)1.8-selective inhibitors; Non-addictive analgesics; Pain.

MeSH terms

Analgesics / chemistry
Analgesics / pharmacology
Analgesics / therapeutic use
Animals
HEK293 Cells
Humans
Mice
NAV1.7 Voltage-Gated Sodium Channel*
Niacinamide* / pharmacology
Niacinamide* / therapeutic use
Pain / drug therapy

Substances

Niacinamide
NAV1.7 Voltage-Gated Sodium Channel
Analgesics