Inhibition of Na(V)1.7: the possibility of ideal analgesics

The selective inhibition of Na(V)1.7 is a promising strategy for developing novel analgesic agents with fewer adverse effects. Although the potent selective inhibition of Na(V)1.7 has been recently achieved, multiple Na(V)1.7 inhibitors failed in clinical development. In this review, the relationship between preclinical in vivo efficacy and Na(V)1.7 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.