Discovery of Selective Inhibitors of NaV1.7 Templated on Saxitoxin as Therapeutics for Pain

• Published in: ACS medicinal chemistry letters Vol. 13; no. 11; pp. 1763 - 1768
• Main Authors: Pajouhesh, Hassan, Delwig, Anton, Beckley, Jacob T., Klas, Sheri, Monteleone, Dennis, Zhou, Xiang, Luu, George, Du Bois, J., Hunter, John C., Mulcahy, John V.
• Format: Journal Article
• Language: English
• Published: American Chemical Society 10.11.2022
• Subjects: Letter; Nav1.7; non-opioid; pain; sodium channel; saxitoxin
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.2c00378

The voltage-gated sodium channel isoform NaV1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal muscle and the heart, poses a significant challenge to the development of small molecule inhibitors of NaV1.7. Most inhibitors of NaV1.7 disclosed to date belong to a class of aryl and acyl sulfonamides that preferentially bind to an inactivated conformation of the channel. By taking advantage of a sequence variation unique to primate NaV1.7 in the extracellular pore of the channel, a series of bis-guanidinium analogues of the natural product, saxitoxin, has been identified that are potent against the resting conformation of the channel. A compound of interest, 25, exhibits >600-fold selectivity over off-target sodium channel isoforms and is efficacious in a preclinical model of acute pain.