Discovery of Novel Nav1.7-Selective Inhibitors with the 1H-Indole-3-Propionamide Scaffold for Effective Pain Relief
Gaoang Wang,
Hang Wu,
Yingying Wang,
Xiangying Liu,
Shuijiao Peng,
Wenxing Wang,
Meijing Wu,
Yifei Liu,
Ercheng Wang,
Zhe Wang,
Lei Xu,
Xiaojian Wang,
Wei Yang,
Haiyi Chen,
Xi Zhou,
Tingjun Hou
Affiliations
Gaoang Wang
College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou, Zhejiang 310058, China.
Hang Wu
The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, and Peptide and Small Molecule Drug R&D Platform, Furong Laboratory,
Hunan Normal University, Changsha 410081, Hunan, China.
Yingying Wang
Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, China.
Xiangying Liu
State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Shuijiao Peng
The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, and Peptide and Small Molecule Drug R&D Platform, Furong Laboratory,
Hunan Normal University, Changsha 410081, Hunan, China.
Wenxing Wang
The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, and Peptide and Small Molecule Drug R&D Platform, Furong Laboratory,
Hunan Normal University, Changsha 410081, Hunan, China.
Meijing Wu
The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, and Peptide and Small Molecule Drug R&D Platform, Furong Laboratory,
Hunan Normal University, Changsha 410081, Hunan, China.
Yifei Liu
College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou, Zhejiang 310058, China.
School of Pharmacy,
Hangzhou Normal University, Hangzhou 311121, Zhejiang, China.
Lei Xu
Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering,
Jiangsu University of Technology, Changzhou 213001, Jiangsu, China.
Xiaojian Wang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica,
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Wei Yang
Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, China.
Haiyi Chen
College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou, Zhejiang 310058, China.
Xi Zhou
The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, and Peptide and Small Molecule Drug R&D Platform, Furong Laboratory,
Hunan Normal University, Changsha 410081, Hunan, China.
Tingjun Hou
College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou, Zhejiang 310058, China.
Nav1.7 is considered a promising target for developing next-generation analgesic drugs, given its critical role in human pain pathologies. Although most reported inhibitors with strong in vitro activity and high selectivity share the aryl sulfonamide scaffold, they failed to demonstrate marked clinical efficacy. Therefore, exploring new Nav1.7-selective antagonists is quite urgent to the development of next-generation analgesic drugs. Here, we report a highly effective 1H-indole-3-propionamide inhibitor, WN2, identified through an integrated drug discovery strategy. Notably, the structure of WN2 is quite different from previously reported aryl sulfonamide inhibitors. Molecular dynamics simulations and experimental findings reveal that the R configuration of WN2 (WN2-R) is the preferred form (IC50 = 24.7 ± 9.4 nM) within the VSDIV pocket of Nav1.7. WN2-R exhibits impressive analgesic effects in acute and chronic inflammatory pain, as well as neuropathic pain models in mice. Additionally, it displays favorable subtype selectivity and positive drug safety in acute toxicity studies. Pharmacokinetic studies indicate that WN2-R has high bioavailability (F = 20.29%), highlighting its considerable potential for drug development. Our study establishes WN2-R as a novel Nav1.7-selective inhibitor with a unique structural scaffold, offering a promising candidate for the next generation of analgesic drugs.
