Effects of SZV-2649, a new multiple ion channel inhibitor mexiletine analogue

Abstract

The antiarrhythmic and cardiac electrophysiological effects of SZV-2649 that contains a 2,6-diiodophenoxy moiety but lacks the benzofuran ring system present in amiodarone, were studied in mammalian cell line, rat and dog cardiac preparations. SZV-2649 exerted antiarrhythmic effects against coronary artery occlusion/reperfusion induced ventricular arrhythmias in rats and in acetylcholine- and burst stimulation induced atrial fibrillation in dogs. SZV-2649 inhibited hERG and GIRK currents in HEK cells (IC50: 342 and 529 nM, respectively). In canine ventricular myocytes, SZV-2649 (10 µM) decreased the densities of IKr, and Ito outward and INaL and ICaL inward currents. The compound (2.5–10 µM) elicited Class IB type Vmax reducing and Class III type action potential duration prolonging effects in dog right ventricular muscle preparations. In canine atrial muscle, SZV-2629 (2.5–10 µM) moderately prolonged action potential duration and this effect was greatly augmented in preparations pretreated with 1 µM carbachol. In conclusion, SZV-2649, has antiarrhythmic effects based on its multiple ion channel blocking properties. Since its chemical structure substantially differs from that of amiodarone, it is expected that SZV-2649 would exhibit fewer adverse effects than the currently used most effective multichannel inhibitor drug amiodarone and may be a promising molecule for further development.