ATI-2001

Antiarrhythmic agents with amiodarone-like electrophysiological actions, but with a more favorable pharmacokinetic profile than amiodarone would be extremely useful for the treatment of many tachyarrhythmias. We designed a series of amiodarone homologs with an alkyl ester group at position 2 of the benzofurane moiety. It was hypothesized that the electrophysiological and pharmacokinetic properties of these compounds are closely related to the size and branching of the ester group. The magnitude and time course of electrophysiological effects caused by methyl (ATI-2001), ethyl (ATI-2010), isopropyl (ATI-2064), sec-butyl (ATI-2042), and neopentyl (ATI-2054) homologs, and their common metabolite (ATI-2000) were investigated in guinea pig isolated heart. In paced hearts (atrial cycle length = 300 ms), each homolog (1 microM) was infused for 90 min followed by a 90-min washout. The stimulus-to-atrium (St-A), atrium-to-His bundle (AH), His bundle-to-ventricle (HV), QRS, and QT intervals, and ventricular monophasic action potential duration at 90% repolarization (MAPD(90)) were measured every 10 min. ATI-2001 and ATI-2064 significantly lengthened the St-A, HV, and QRS intervals, whereas ATI-2042 and ATI-2054 prolonged only the St-A interval. All compounds except the metabolite prolonged the AH interval. The relative rank order for the homologs to lengthen ventricular repolarization (MAPD(90)) was ATI-2042 > or = 2001 = 2010 = 2064 > 2054 > or = 2000. The metabolite was electrophysiologically inactive. Thus, modification of the benzofurane moiety ester group size and branching markedly altered the magnitude and time course of the electrophysiological effects caused by the ATI compounds. The different structure-activity relationships among the amiodarone homologs may have important consequences for further development of amiodarone-like antiarrhythmic agents.

We recently demonstrated that the short-acting analog of amiodarone, ATI-2001, caused favorable effects in guinea pig ventricular myocardium on electrophysiological substrates underlying tachyarrhythmia initiation, perpetuation, and termination. Here, the acute effects of 1.0 microM ATI-2001 and 1.0 microM amiodarone (90-min infusion followed by 90-min washout period) on atrial and atrioventricular (AV) nodal electrophysiological properties were studied in guinea pig isolated hearts. Neither ATI-2001 nor amiodarone significantly prolonged atrial conduction time. Compared with amiodarone, ATI-2001 caused significantly more rapid and greater prolongation of atrial monophasic action potential duration at 90% repolarization (maximal change 21.4 +/- 3.7 versus 19.0 +/- 4.0 ms) and atrial effective refractory period (ERP, 27.8 +/- 6.1 versus 9.2 +/- 2.3 ms). Shortening of the atrial cycle length from 250 to 200 ms did not significantly alter drug-induced changes in atrial repolarization and refractoriness. ATI-2001 prolonged the atrium-to-His bundle interval (22.1 +/- 2.6 versus 8.8 +/- 2.3 ms), His bundle-to-ventricle interval (2.8 +/- 0.4 versus 0.9 +/- 0.3 ms), AV nodal ERP (72.5 +/- 7.3 versus 31.4 +/- 4.1 ms), and Wenckebach cycle length (69.6 +/- 5.2 versus 35.8 +/- 4.1 ms) significantly more than did amiodarone. Unlike amiodarone, the effects of ATI-2001 were markedly reversed upon discontinuation of drug infusion. Given these data, ATI-2001 should not only be useful for terminating ongoing and preventing reoccurrence of atrial tachyarrhythmias but also to treat supraventricular tachycardias involving the AV node and to control ventricular rate during atrial tachyarrhythmias. Whether the observed differences in the pharmacokinetic properties render ATI-2001 superior to amiodarone in acute tachyarrhythmia management and less likely to accumulate into tissues during chronic therapy remains to be established.