IKr Channel Blockers: Novel Antiarrhythmic Agents

There have been extensive efforts to develop IKr channel blockers as a new antiarrhythmic agent for atrial or ventricular fibrillation, since it was demonstrated that selective blockade of the rapidly activating delayed rectifier K+ channel (IKr) in the heart is not deleterious for the total mortality in fatal ventricular arrhythmia patients. Among them, dofetilide and KCB-328 blocks the IKr specifically. Therefore, it increases the action potential duration (APD) selectively. Ibutilide, trecetilide, nifekalant, dronedarone, BRL-32872, H345 / 52 and ersentilide block the IKr. However, they modify also other cardiac channels or receptors. The frequency dependence of the compounds in prolonging the APD varies from the strong reversed tendency of dofetilide to the relatively neutral profile of KCB-328 and BRL-32872. Every compound reported so far has a proarrhythmic potential of torsade de pointes induction under certain conditions, although depending on the structure, the intensity may be somewhat different. In the coming decade, efforts to improve the reverse frequency dependence profile of the IKr blockers by optimizing the onset and recovery time constant of the HERG block (e.g. KCB-328, vesnarinone) or the balance between the block of IKr and Ca++ channels in the heart (e.g. BRL-32872, H 345 / 52) to eliminate the proarrhythmic potential of the currently known IKr blockers are warranted. Further trials are also needed to discover more favorable compounds with multiple receptors including IKr (e.g. nifekalant, dronedarone) for treating ventricular arrhythmias.