A novel Nav1.7, Nav1.8, and Nav1.9 blocker, ANP-230, has broad analgesic efficacy in preclinical pain models with favorable safety margins.

Chronic pain, such as neuropathic and inflammatory pain, poses significant challenges to society. Current treatments are often ineffective and have central side effects and drug dependence issues, highlighting the unmet medical needs for new drugs with novel mechanisms. Nav1.7, Nav1.8, and Nav1.9 voltage-gated sodium channels are predominantly expressed in peripheral nociceptive neurons and involved in pathological pain, making them promising targets for developing effective and safe analgesics. Consequently, the research and development of selective antagonists for each subtype have been actively pursued. Recently, a Nav1.8 blocker has been approved for postoperative acute pain, and it is anticipated to offer a new therapeutic option. On the other hand, the optimal approach to suppress hyperexcitability in pathological pain pathways and achieve satisfactory analgesia in chronic pain conditions remains unclear. In this study, ANP-230, a clinical compound which equipotently blocks all of Nav1.7, Nav1.8, and Nav1.9 by a state-independent mechanism, demonstrated dose-dependent analgesic efficacies in a series of neuropathic and inflammatory pain models, with increased potency upon repeated administration. It showed negligible motor function impairment in rotarod and locomotor test, reflecting its peripheral Nav subtypes selectivity and low penetration to central nervous system. Furthermore, when concurrently administered with pregabalin and morphine, ANP-230 potentiated their anti-allodynic effects. Hence, ANP-230 has potential as a broad-spectrum analgesic with a favorable safety profile. Our study sheds light on a strategy utilizing a peripherally restricted compound that preferentially inhibits Nav1.7, Nav1.8, and Nav1.9 in chronic pain conditions.