Ion channel modulating activity method
Methods, compositions, dosing regimes, and routes of administration for the treatment or prevention of arrhythmias. In these methods, arrythmias (e.g. atrial fibrillation, atrial flutter, early afterdepolarizations and prolongation of QT interval) may be reduced or eliminated by administering ion channel modulating compounds to a subject in need thereof. The ion channel modulating compounds may be cycloalkylamine ether compounds, particularly cyclohexylamine ether compounds. Also described are compositions of ion channel modulating compounds and drugs which induce early afterdepolarizations, prolongation of QT interval and/or Torsades de Pointes.
1. A method of identifying an ion channel modulating compound useful for the treatment of atrial fibrillation comprising identifying a compound that inhibits Kv potassium channels expressed in HEK cells at IC 50 concentrations greater than about 8 μM, and further exhibits a 4 to 10-fold increase in rate-dependent inhibition of a sodium channel over a physiologically and pathophysiologically significant range of heart rates between about 0.25 to about 20 Hz, and further exhibits a 3x or greater decrease in IC 50 of voltage-dependent inhibition of sodium channel current from about 100 μM to about 30 μM, in the resting potential range between about −120 mV to about −60 mV, and does not inhibit hERG channels, except at IC 50 concentrations greater than 10 μM.