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 NaV1.7 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 NaV1.7 inhibitor in vitro and exhibited antinociceptive effects in vivo. The identification of 36c not only provides a new insight into the discovery of selective NaV1.7 inhibitors, but also may hold premise for pain therapy.

Automated summary

Chronic pain severely impacts quality of life and requires effective treatments. This study designed, synthesized, and evaluated a series of acyl sulfonamide derivatives targeting NaV1.7 for their antinociceptive activities. Among them, compound 36c was identified as a selective and potent NaV1.7 inhibitor in vitro and showed antinociceptive effects in vivo. The discovery of 36c provides new insights into selective NaV1.7 inhibitors and potential pain therapies.