Inhibition of Na1.7: the possibility of ideal analgesics.

The selective inhibition of Na1.7 is a promising strategy for developing novel analgesic agents with fewer adverse effects. Although the potent selective inhibition of Na1.7 has been recently achieved, multiple Na1.7 inhibitors failed in clinical development. In this review, the relationship between preclinical efficacy and Na1.7 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 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.