LTGO-33

LTGO-33 is a preclinical, highly selective small-molecule inhibitor of the voltage-gated sodium channel NaV1.8 (SCN10A), developed by Latigo Biotherapeutics as a non-opioid analgesic for pain disorders.[3][5][10][13] In electrophysiology studies, LTGO-33 inhibits human NaV1.8 with nanomolar potency and exhibits more than 600-fold selectivity over other human NaV isoforms (NaV1.1–NaV1.7 and NaV1.9), while showing pronounced species selectivity for primate over rodent and canine NaV1.8.[3][5][9] Mechanistically, LTGO-33 is a state-independent blocker that binds to a novel site in the extracellular cleft of the second voltage-sensing domain (VSDII), stabilizing the deactivated state and preventing channel opening, with inhibition relieved by strong depolarization but not during physiological action-potential trains.[3][5][6][12] By selectively suppressing NaV1.8-mediated firing in human dorsal root ganglion neurons, including gain-of-function variants associated with painful neuropathies, LTGO-33 exemplifies a new pharmacologic paradigm aimed at treating acute and chronic pain while minimizing off-target effects on cardiac, respiratory, and central nervous system sodium channels.[3][5][10][11][13]