Discovery of Novel Na1.7-Selective Inhibitors with the 1-Indole-3-Propionamide Scaffold for Effective Pain Relief.

Na1.7 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 Na1.7-selective antagonists is quite urgent to the development of next-generation analgesic drugs. Here, we report a highly effective 1-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 (IC = 24.7 ± 9.4 nM) within the VSDIV pocket of Na1.7. 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 ( = 20.29%), highlighting its considerable potential for drug development. Our study establishes WN2-R as a novel Na1.7-selective inhibitor with a unique structural scaffold, offering a promising candidate for the next generation of analgesic drugs.