2. Academic Validation
  3. Design, synthesis, structure-activity relationship (SAR) and analgesic effect studies of novel arylsulfonamides as selective Nav1.7 inhibitors

Design, synthesis, structure-activity relationship (SAR) and analgesic effect studies of novel arylsulfonamides as selective Nav1.7 inhibitors

  • Eur J Med Chem. 2025 Dec 5:299:118069. doi: 10.1016/j.ejmech.2025.118069.
Ruokun Wu 1,  Wenfeng Chen 1,  Xueyuan Wang 2,  Xinran Ye 1,  Hang Miao 2,  Jingmiao Shi 3,  Meng Lei 4,  Yongqiang Zhu 5
Affiliations

Affiliations

  • 1 College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing, 210037, PR China.
  • 2 College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing, 210046, PR China.
  • 3 Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing, 210033, PR China.
  • 4 College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing, 210037, PR China; Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing, 210033, PR China. Electronic address: hk-lm@163.com.
  • 5 College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing, 210046, PR China; Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing, 210033, PR China. Electronic address: zhyqscu@hotmail.com.
PMID: 40882438 DOI: 10.1016/j.ejmech.2025.118069
Abstract

Chronic pain has become a major factor affecting the quality of human life. Nav1.7 is a subtype of neuronal voltage-gated Sodium Channel. Its mutation is closely related to pain syndrome. By inhibiting the function of Nav1.7, it can effectively relieve pain. As a result, it has been extensively researched as a hot target for pain management. In this manuscript, a series of new arylsulfonamide compounds based on Nav1.7 were designed and synthesized. The biological properties of these compounds were assessed through various experiments, including in vitro and in vivo evaluations, microsomal stability, selectivity, hERG and pharmacokinetic studies. Compound 50 was found to show favorable microsomal stability, in vivo safety, high selectivity and a low potential risk of cardiotoxicity. Further in vivo studies showed that compound 50 had a faster onset of action and better analgesic efficacy in several pain models than positive control. In addition, molecular docking results showed that compound 50 formed 2 hydrogen bonds and π-π stacking interactions with amino acid residues in the lipid exposed pocket of Nav1.7. These results suggested that compound 50 might be a potent candidate for the treatment of neuropathic pain.

Keywords

Analgesic effect; Chronic pain; Nav1.7; Pharmacokinetics; Structure-activity relationship.

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