JTV-519

Conversion and prevention of atrial fibrillation (AF) are essential requirements for its treatment. Abnormal leakage of calcium from the sarcoplasmic reticulum via the ryanodine receptor 2 (RyR2) during diastole is considered a major cause of AF. Although catheter ablation has made it possible to stop persistent AF, it does not address recurrence. In this context, we describe the additional pharmacological and antiarrhythmic effects of the RyR2 inhibitor M201-A, including the results of a phase I study. M201-A inhibited G-protein-gated atrial K⁺ channel at an IC₅₀ value of 0.35 μM, which was associated with a 38% increase in the atrial effective refractory period (ERP) and high atrial selectivity with an atrial ERP/ventricular ERP of 5.7. M201-A inhibited rapid component of the delayed rectifier potassium current (IC₅₀ value of 0.43 μM) but induced only a limited prolongation in the action potential duration in rabbit ventricular cells and human induced pluripotent stem cell-derived cardiomyocytes. M201-A is an R-enantiomer of the active metabolite M201-R of K201. After orally administering 540 mg K201 to patients with AF, the unbound drug concentration of M201-R was 30-fold higher (approximately 15-fold for M201-A) than that of K201, and AF was converted in 6 of the 12 patients (50%) during the first 2 hours following administration. M201-A was the main contributor with a stronger bioactive metabolite than M201-B (S-enantiomer) and M201-R. Furthermore, M201-A was 5-fold more biologically active than K201 in humans due to protein binding rates. These pharmacological properties hold promise as a new therapeutic strategy for AF, particularly the prevention of recurrence after catheter ablation. SIGNIFICANCE STATEMENT: Abnormal leakage of calcium from the sarcoplasmic reticulum via the ryanodine receptor 2 (RyR2) is considered a major cause of atrial fibrillation (AF). M201-A had inhibitory effects on RyR2 and G-protein-gated atrial K⁺ channel. It had high atrial selectivity with limited QT interval corrected by Fridericia's formula prolongation and proarrhythmic risk. It was the most active conversion metabolite when K201 was administered orally in patients with paroxysmal AF. These pharmacological effects of M201-A, combined with its inhibitory actions on RyR2, provide a promising therapeutic option for treating AF.