Sulfonamide Compounds as Voltage Gated Sodium Channel Modulators.

Abstract

Nav1.7 Summary: Maintaining a specific membrane potential is critical to many cellular functions of mammalian cells. The heart, central and peripheral nervous system, and muscle function all depend on the proper regulation and timing of changes in membrane potential. Voltage gatedsodiumchannelsplayakeyroleintheseprocesses.Todate,ninevoltagegatedsodiumchannels,Nav1.1toNav1.9,havebeen identified, and improper NaV activity can lead to a number of negative health consequences. Nav1.7, for example, has been linked to pain sensation. Loss of function mutations of this ion channel have been documented in humans and linked to congenital insensitivity to painful stimuli. Increased Nav1.7, however, has been associated with increased sensitivity to pain. These observations indicate that Nav1.7 blockade may be a viable method of treating chronic pain. Compounds such as Raxatrigine (CNV1014802), a Nav1.7 blocker that recently completed phase II clinical trials for the treatment of lumbar radiculopathy (sciatica),appeartohavevalidatedthishypothesis.Thepresentdisclosuredescribesaseriesofsulfonamidescapableofmodulating Nav1.7 activity and their use as treatment for pain and pain related disorders.