Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models

We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNa(V)1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNa(V)1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of Na(V)1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNa(V)1.7 as a drug target for the treatment of pain.