Discovery of Novel Na_v1.7-Selective Inhibitors with the 1H-Indole-3-Propionamide Scaffold for Effective Pain Relief.

ABSTRACT: Na_v1.7 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 Na_v1.7-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

SUBMITTER: Wang G 

PROVIDER: S-EPMC11775380 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature