Design, Synthesis, and Biological Evaluation of Novel Biphenyl Derivatives with Therapeutic Potential for Atrial Fibrillation by Synergistically Inhibiting NaV1.5 Late Na+ Current and K+ Current.

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.