Compound 8b demonstrated potent IKr (IC50 = 1.5 μM) and late INa suppression (IC50 = 2.5 μM), showing antiarrhythmic efficacy in an ex vivo rabbit model of atrial fibrillation.
Does compound 8b demonstrate antiarrhythmic efficacy and treat doxorubicin-induced heart failure in preclinical models?
Compound 8b is a promising new class III antiarrhythmic candidate that synergistically inhibits IKr and late INa, showing efficacy in preclinical models of AF and heart failure without the adverse effects of dronedarone.
Abstract To overcome the side effects of conduction block and QT prolongation associated with antiatrial fibrillation (AF) drug dronedarone, a novel class of dual IKr and late sodium current (late INa) inhibitors was developed through computational modeling, chemical modification, and electrophysiological screening. Lead compound 8b retained potent IKr inhibition (IC50 = 1.5 μM) comparable to dronedarone. Crucially, 8b avoided dronedarone’s peak INa inhibition while enhancing late INa suppression (IC50 = 2.5 μM) to counteract excessive QT prolongation and avoid conduction block. Compound 8b exhibited favorable pharmacokinetic properties (T1/2 = 5.02 h, F = 110% in mice, p.o.) and high ion channel selectivity. In an ex vivo rabbit heart model of AF, 8b demonstrated antiarrhythmic efficacy. Furthermore, 8b was effective in treating doxorubicin-induced heart failure in mice, a condition where dronedarone shows no therapeutic benefit. Collectively, 8b could serve as a potential new class III antiarrhythmic candidate.
Liao et al. (Fri,) conducted a other in Atrial fibrillation. Compound 8b vs. Dronedarone was evaluated on IKr and late INa inhibition, antiarrhythmic efficacy. Compound 8b demonstrated potent IKr (IC50 = 1.5 μM) and late INa suppression (IC50 = 2.5 μM), showing antiarrhythmic efficacy in an ex vivo rabbit model of atrial fibrillation.
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