Discovery of selective Na1.8 inhibitors based on 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain.

The Na1.8 channel is a genetically validated target for pain and it is mostly expressed in the peripheral nervous system. Based on the disclosed structures of Na1.8-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 (IC = 50.18 ± 0.04 nM) in HEK293 cells stably expressing human Na1.8 channels, it showed potent inhibitory activity in DRG neurons and isoform selectivity (>200-fold against human Na1.1, Na1.5 and Na1.7 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.