From Scaffold Optimization to a Promising Lead: Discovery of a Novel Roemerine Analogue, a Multichannel Antiarrhythmic with Low hERG Liability and Functional Restoration Capacity

This study identified 6–24, a novel antiarrhythmic lead derived from the roemerine scaffold, which exhibited a distinctive multichannel blockade profile targeting Nav1.5 and Cav1.2, while demonstrating only weak inhibition of hERG. This gentle multitarget profile avoided excessive single-channel blockade associated with proarrhythmic drugs, conferring low QT prolongation risk, a key advantage over agents like verapamil. Patch-clamp and iPSC-cardiomyocyte MEA confirmed prolonged action potentials and reduced conduction velocity. Multielectrode mapping in isolated hearts further revealed that the compound dose-dependently prolonged ventricular activation time and reduced conduction velocity, accompanied by a decrease in the heart rate, without significantly altering the QTc interval. Pharmacokinetic analysis further established that this active concentration could be achieved clinically. Beyond electrophysiological modulation, 6–24 uniquely restored cardiac function in vivo, normalizing ventricular dimensions and hemodynamics. With integrated efficacy, safety, and functional restoration, 6–24 represented a promising multitarget candidate for ventricular arrhythmia therapy.