The treatment of pain remains a large unmet medical need. Current therapies suffer from a combination of insufficient efficacy and exposure to significant safety concerns. The voltage gated sodium channel, NaV1.7 plays a central role in the function of peripheral nociception and is supported by remarkable human genetics. Loss-of-function mutations in the SCN9A gene in humans result in congenital insensitivity to pain with little or no effect on motor or cognitive function. We identified a novel class of inhibitors that are highly potent and selective for hNaV1.7. Through ligand-based drug design we optimized physiochemical properties of a novel triazole scaffold, to enhance in vivo unbound drug concentrations. GNE-131 demonstrates efficacy in a transgenic mouse model expressing hNaV1.7 with an inherited erythromelalgia mutation.

Identification of GNE-131: A potent and selective hNaV1.7 inhibitor for the treatment of pain

249th National Meeting (2015)

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