ELECTROPHYSIOLOGIC ACTIVITY AND ANTIARRHYTHMIC EFFICACY OF CK-3579, A NEW CLASS-III ANTIARRHYTHMIC AGENT WITH BETA-ADRENERGIC BLOCKING PROPERTIES

CK-3579 (N-[4-[2-hydroxy-3-[[2-[4-(1H inidazol-1-yl)phenoxy]ethyl]amino]propoxy]phenyl]-methansulfonamide, HCL-[RS]), is a new class III antiarrhythmic agent with beta-adrenoceptor blocking properties shown to be effective in preventing ventricular arrhythmias in experimental animals. We examined the beta1- and beta2- adrenoceptor binding properties, cellular electrophysiology, and antiarrhythmic efficacy of CK-3579 and the two enantiomers CK-4000 (S) and CK-4001 (R). Both CK-3579 and CK-4000 were equipotent in displacing [H-3]dihydroalprenolol from cardiac membranes (IC50 = 2.4 +/- 0.3 and 1.7 +/- 0.4 muM, respectively) and were approximately 23-59 times more selective for the heart receptor than the lung receptor. The IC50 for CK-4001 at the beta1-adrenoceptor was 38.1 +/- 8 muM and > 100 muM at the beta2-adrenoceptor. In isolated canine Purkinje fibers and ventricular muscle preparations, all three compounds increased action potential duration at 95% repolarization (APD95) with equal potency, having an average EC20 of approximately 1 muM in Purkinje fiber and 2 muM in ventricular muscle. No significant effects were observed on any other action potential (AP) parameters. In Purkinje fibers with APs shortened by isoproterenol, the class III activity of CK-4000 was significantly greater than that of CK-4001. CK-4000 inhibits the potassium delayed rectifier current I(k) in a concentration-dependent manner in isolated feline ventricular myocytes. The IC50 for inhibition of fully activated current was 0.4 +/- 0.2 muM. Steady-state currents negative to -20 mV were unchanged by CK-4000, but the ''hump'' in the outward current between -20 and +30 mV was flattened. Both CK-3579 and CK-4000 were effective in preventing programmed electrical stimulation-induced ventricular arrhythmias in dogs with infarcts. The mean effective dose of CK-3579 after either intravenous (i.v.) or oral administration was 1 and 8 mg/kg, respectively. In halothane-anesthetized dogs, both CK3579 and CK-4000 were effective in preventing epinephrine-induced ventricular arrhythmias at -1 mg/kg i.v. CK-4001, however, was ineffective at less-than-or-equal-to 3 mg/kg i.v. CK3579 and CK-4000 have significant class III effects in isolated canine and feline tissues and antiarrhythmic efficacy in ventricular arrhythmia models. In addition to the class III properties, these compounds also block the beta-adrenoceptor with greater affinity for the beta1-adrenoceptor subtype. Thus, CK-3579 and CK-4000 might be useful in treatment of malignant reentrant arrhythmias, especially when sympathetic tone is increased.