Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaV1.7

Voltage-gated sodium ion channel subtype 1.7 (NaV1.7) is a high interest target for the discovery of non-opioid analgesics. Compelling evidence from human genetic data, particularly the finding that persons lacking functional NaV1.7 are insensitive to pain, has spurred considerable effort to develop selective inhibitors of this Na+ ion channel target as analgesic medicines. Recent clinical setbacks and disappointing performance of preclinical compounds in animal pain models, however, have led to skepticism around the potential of selective NaV1.7 inhibitors as human therapeutics. In this Perspective, we discuss the attributes and limitations of recently disclosed investigational drugs targeting NaV1.7, and review evidence that, by better understanding the requirements for selectivity and target engagement, the opportunity to deliver effective analgesic medicines targeting NaV1.7 endures.