Design, synthesis, structure-activity relationship (SAR) and analgesic effect studies of novel arylsulfonamides as selective Nav1.7 inhibitors.

Chronic pain has become a major factor affecting the quality of human life. Nav1.7 is a subtype of neuronal voltage-gated sodium channel. Its mutation is closely related to pain syndrome. By inhibiting the function of Nav1.7, it can effectively relieve pain. As a result, it has been extensively researched as a hot target for pain management. In this manuscript, a series of new arylsulfonamide compounds based on Nav1.7 were designed and synthesized. The biological properties of these compounds were assessed through various experiments, including in vitro and in vivo evaluations, microsomal stability, selectivity, hERG and pharmacokinetic studies. Compound 50 was found to show favorable microsomal stability, in vivo safety, high selectivity and a low potential risk of cardiotoxicity. Further in vivo studies showed that compound 50 had a faster onset of action and better analgesic efficacy in several pain models than positive control. In addition, molecular docking results showed that compound 50 formed 2 hydrogen bonds and π-π stacking interactions with amino acid residues in the lipid exposed pocket of Nav1.7. These results suggested that compound 50 might be a potent candidate for the treatment of neuropathic pain.