Development of new Kir2.1 channel openers from propafenone analogues

Background and Purposes: Reduced inward rectifier potassium channel (K(ir)2.1) functioning is associated with heart failure and may cause Andersen-Tawil Syndrome, among others characterized by ventricular arrhythmias. Most heart failure or Andersen-Tawil Syndrome patients are treated with beta-adrenoceptor antagonists (beta-blockers) or sodium channel blockers; however, these do not specifically address the inward rectifier current (I-K1) nor aim to improve resting membrane potential stability. Consequently, additional pharmacotherapy for heart failure and Andersen-Tawil Syndrome treatment would be highly desirable. Acute propafenone treatment at low concentrations enhances I-K1 current, but it also exerts many off-target effects. Therefore, discovering and exploring new I-K1-channel openers is necessary. Experimental Approach: Effects of propafenone and 10 additional propafenone analogues were analysed. Currents were measured by single-cell patch-clamp electrophysiology. K(ir)2.1 protein expression levels were determined by western blot analysis and action potential characteristics were further validated in human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMCs). Molecular docking was performed to obtain detailed information on drug-channel interactions. Key Results: Analogues GPV0019, GPV0057 and GPV0576 strongly increased the outward component of I-K1 while not affecting the K(ir)2.1 channel expression levels. GPV0057 did not block I-Kr at concentrations below 0.5 mu mol L-1 nor Na(V)1.5 current below 1 mu mol L-1. Moreover, hiPSC-CMC action potential duration was also not affected by GPV0057 at 0.5 and 1 mu mol L-1. Structure analysis indicates a mechanism by which GPV0057 might enhance K(ir)2.1 channel activation. Conclusion and Implications: GPV0057 has a strong efficiency towards increasing I-K1, which makes it a good candidate to address I-K1 deficiency-associated diseases.