Discovery of selective NaV1.8 inhibitors based on 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl nicotinamide scaffold for the treatment of pain

The NaV1.8 channel is a genetically validated target for pain and it is mostly expressed in the peripheral nervous system. Based on the disclosed structures of NaV1.8-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 (IC50 = 50.18 ± 0.04 nM) in HEK293 cells stably expressing human NaV1.8 channels, it showed potent inhibitory activity in DRG neurons and isoform selectivity (>200-fold against human NaV1.1, NaV1.5 and NaV1.7 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. A series of novel NaV1.8 inhibitors based on 5-chloro-2-(4,4-difluoroazepan-1-yl)-6-methyl nicotinamide scaffold were designed and synthesized. Based on SAR studies and in vivo evaluation, compound 2c was identified as the most promsing lead compound with a moderate inhibitory potency (hNaV1.8 IC50 = 50.18 ± 0.04 nM), excellent selectivity, reasonable PK properties, and increased potency in a post-surgical mouse model (30 mg/kg, p.o.). [Display omitted] •A series of hNaV1.8 inhibitors with bicyclic aromatic fragments were discovered.•Compound 2c exhibited moderate inhibitory activity for hNaV1.8 with the excellent selectivity.•Compound 2c didn't inhibit hERG channels at 40 μM.•Compound 2c showed reasonable PK properties in vivo.•Lead compound 2c alleviated pain conditions at 30 mg/kg in mouse models.