Ion channel modulating activity ii

Abstract

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 .- 52 . (canceled) 
   
   
       53 . An ion channel modulating compound, or solvate or pharmaceutically acceptable salt thereof, having one or more of the following characteristics:
 (a) exhibits a 4 to 10-fold increase in rate-dependent inhibition of a sodium channel between 0.25 and 20 Hz with an activated:closed potency ratio of about 10:1 when pulsed from about −100 mV to about −30 mV at about 10 Hz, and further inhibits Kv potassium channels expressed in HEK cells at IC 50  concentrations greater than about 8 μM and Kv1 subfamily of channels by predominantly rate- and use-independent open channel inhibition, but does not inhibit hERG channels, except at IC 50  concentrations greater than about 10 μM;   (b) exhibits a 3× or greater decrease in the 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 to about −60 mV, and further inhibits Kv potassium channels at IC 50  concentrations of greater than about 8 μM when expressed in HEK cells, and inhibits Kv1 subfamily of channels by predominantly rate-independent and use-independent open channel inhibition, but does not inhibit hERG channels, except at IC 50  concentrations greater than about 10 μM;   (c) 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, and further exhibits a 3× or greater decrease in the 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 to about −60 mV, and further exhibits state-dependent inhibition of sodium channels with an activated:closed potency ratio of about 10:1 when pulsed from about −100 mV to about −30 mV at about 10 Hz., and rapidly associates and dissociates from sodium channels with a recovery time constant of inhibition of less than about 1.5 s, but does not substantially slow conduction or alter the voltage time course of repolarization in ventricular muscle or Purkinje fibers;   (d) exhibits a 4 to 10-fold increase in rate-dependent inhibition of a sodium channel over a range of heart rates between about 0.25 to about 20 Hz, and further exhibits a 3× 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 further exhibits state-dependent inhibition of sodium channels with an activated:closed potency ratio of about 10:1 when pulsed from about −100 mV to about −30 mV at about 10 Hz, and further produces less than a 10% increase in cardiac QRS duration at physiological heart rates;   (e) 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 3× 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 affects atrial repolarizing currents but has substantially no effect on ventricular tissue under normal conditions;   (f) prolongs atrial refractoriness and AV nodal conduction but has substantially no effect on ventricular tissues and inhibits Kv potassium channels by predominantly rate- and use-independent open channel inhibition at IC 50  concentrations greater than about 8 μM when expressed in HEK cells, and further does not inhibit hERG channels, except at IC 50  concentrations greater than 10 μM, and further does not inhibit L-type calcium channels except at IC 50  concentrations greater than about 100 μM;   (g) produces a selective increase in atrial ERP and prolonged atrial fibrillation cycle length (AFCL) in AF, but has substantially no effect on normal electrical activity in ventricular tissues, and exhibits a 4 to 10-fold increase in rate-dependent inhibition of a sodium channel between 0.25 and 20 Hz, and further exhibits a 3× 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;   (h) produces a selective increase in atrial ERP and prolonged atrial fibrillation cycle length (AFCL) in AF, but has substantially no effect on ventricular tissues and produces less than a 10% increase in cardiac QRS duration at physiological heart rates, and that exhibits state-dependent inhibition of sodium channels with an activated:closed potency ratio of about 10:1 when pulsed from about −100 mV to about −30 mV at about 10 Hz., and that rapidly associates and dissociates from sodium channels with a recovery time constant of inhibition of less than about 1.5 s;   (i) 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 3× 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;   (j) inhibits Kv potassium channels expressed in HEK cells at IC 50  concentrations greater than about 8 μM, and further does not inhibit hERG channels, except at IC 50  concentrations greater than 10 μM, and affects atrial repolarizing currents but has substantially no effect on ventricular tissue; and   (k) prolongs atrial refractoriness and AV nodal conduction but has substantially no effect on ventricular tissues and inhibits potassium channels, including I KACh , at IC 50  concentrations greater than about 8 μM in atrial cells, and further does not inhibit hERG channels, except at IC 50  concentrations greater than 10 μM, and further does not inhibit L-type calcium channels except at IC 50  concentrations greater than about 100 μM.   
   
   
       54 . The ion channel modulating compound, or solvate or pharmaceutically acceptable salt thereof, of  claim 53  that inhibits Kv potassium channels expressed in HEK cells at IC 50  concentrations greater than about 8 μM and further that 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 that exhibits a 3× 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 that does not inhibit hERG channels, except at IC 50  concentrations greater than 10 μM. 
   
   
       55 . The ion channel modulating compound of  claim 54 , or solvate or pharmaceutically acceptable salt thereof, that inhibits Kv1 subfamily of channels by rate-independent and use-independent open channel inhibition. 
   
   
       56 . The ion channel modulating compound of  claim 55 , or solvate or pharmaceutically acceptable salt thereof, that inhibits hERG and Kv1.5 channel currents with a potency that is about 2× the IC 50  potency for inhibition of Kv4 channels in HEK cells expressing these channels. 
   
   
       57 . A composition comprising the ion channel modulating compound, or solvate or pharmaceutically acceptable salt thereof, of  claim 53 .