Trecetilide Fumarate

There have been extensive efforts to develop I(Kr) 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 (I(Kr)) in the heart is not deleterious for the total mortality in fatal ventricular arrhythmia patients. Among them, dofetilide and KCB-328 blocks the I(Kr) specifically. Therefore, it increases the action potential duration (APD) selectively. Ibutilide, trecetilide, nifekalant, dronedarone, BRL-32872, H345/52 and ersentilide block the I(Kr). 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 I(Kr) 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 I(Kr) and Ca++ channels in the heart (e.g. BRL-32872, H 345/52) to eliminate the proarrhythmic potential of the currently known I(Kr) blockers are warranted. Further trials are also needed to discover more favorable compounds with multiple receptors including I(Kr) (e.g. nifekalant, dronedarone) for treating ventricular arrhythmias.

A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation. Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue at both slow and fast pacing rates. The potential for producing polymorphic ventricular tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The S-enantiomers generally had less proarrhythmic activity than the corresponding racemates. One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was chosen for further development.