Progress toward the development of a safe and effective agent for treatingreentrant cardiac arrhythmias: Synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential

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