Design, synthesis, and biological evaluation of acyl sulfonamide derivatives with spiro cycles as NaV1.7 inhibitors for antinociception

Chronic pain, as an unmet medical need, severely impacts the quality of life. The voltage-gated sodium channel Na_V1.7 preferentially expressed in sensory neurons of dorsal root ganglia (DRG) serves a promising target for pain therapy. Here, we report the design, synthesis, and evaluation of a series of acyl sulfonamide derivatives targeting Nav1.7 for their antinociceptive activities. Among the derivatives tested, the compound 36c was identified as a selective and potent Na_V1.7 inhibitor in vitro and exhibited antinociceptive effects in vivo. The identification of 36c not only provides a new insight into the discovery of selective Na_V1.7 inhibitors, but also may hold premise for pain therapy.