Identification Of Aryl Sulfonamides As Novel And Potent Inhibitors Of Na(V)1.5

We describe the synthesis and biological evaluation of a series of novel aryl sulfonamides that exhibit potent inhibition of Na(V)1.5. Unlike local anesthetics that are currently used for treatment of Long QT Syndrome 3 (LQT3), the most potent compound (-)-6 in this series shows high selectivity over hERG and other cardiac ion channels and has a low brain to plasma ratio to minimize CNS side effects. Compound (-)-6 is also effective in shortening prolonged action potential durations (APDs) in a pharmacological model of LQT-3 syndrome in pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Unlike most aryl sulfonamide Na-V inhibitors that bind to the channel voltage sensors, these Na(V)1.5 inhibitors bind to the local anesthetic binding site in the central pore of the channel.