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
Weiming Liao, Wei Wang, An Zhang, Bingxun Li, Xi Wang, Chao Tian, Guifang Duan, Liandi Lei, Ziyao Huang, Siyuan Chen, Ruijie Yan, Xiaowei Wang, Liangren Zhang, Lin Wu, Zhuo Huang, Qi SunAbstract
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.