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.