The selective inhibition of NaV1.7 is a promising strategy for developing novel analgesic agents with fewer adverse effects. Although the potent selective inhibition of NaV1.7 has been recently achieved, multiple NaV1.7 inhibitors failed in clinical development. In this review, the relationship between preclinical in vivo efficacy and NaV1.7 coverage among three types of voltage-gated sodium channel (VGSC) inhibitors, namely conventional VGSC inhibitors, sulphonamides and acyl sulphonamides, is discussed. By demonstrating the PK/PD discrepancy of preclinical studies versus in vivo models and clinical results, the potential reasons behind the disconnect between preclinical results and clinical outcomes are discussed together with strategies for developing ideal analgesic agents.
