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

Abstract

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.