Discovery of 1H-Indole-3-Propionamide Derivatives as Potent, Selective and Orally Available NaV1.7 Inhibitors for Pain Treatment.

Dysfunction of the voltage-gated sodium channel NaV1.7 underlies multiple pain-sensitivity disorders, making NaV1.7 inhibition an attractive therapeutic strategy. However, currently available NaV1.7 inhibitors, frequently suffer from limited structural diversity and moderate selectivity. We previously identified a novel indole-based hit that demonstrated modest selectivity toward other sodium channels. Herein, systematic structure-activity relationship studies of 1H-indole-3-propionamide derivatives led to the discovery of compound 56, a potent and subtype-selective NaV1.7 inhibitor. The analgesic mechanism of 56 was elucidated through an electrophysiological evaluation in mouse dorsal root ganglion neurons. Moreover, 56 reduced the risk of human ether-à-go-go-related gene (hERG)-related cardiotoxicity and demonstrated a favorable motor function profile in mice. With acceptable pharmacokinetic properties, oral administration of 56 displayed robust analgesic efficacy across various murine models of acute, chronic inflammatory, and neuropathic pain. The findings of the study highlight a highly promising, orally available lead compound for pain treatment.