Compound 8b, a novel biphenyl derivative that inhibits IKr and late INa without inhibiting peak INa, could serve as a potential new class III antiarrhythmic candidate for atrial fibrillation.
A novel class of dual IKr and late sodium current (late INa) inhibitors was developed to address the conduction block and QT prolongation associated with dronedarone.
Lead compound 8b retained potent IKr inhibition comparable to dronedarone.
Compound 8b avoided dronedarone's peak INa inhibition while enhancing late INa suppression.
Compound 8b showed favorable pharmacokinetic properties in mice and high ion channel selectivity.
Compound 8b showed antiarrhythmic efficacy in an ex vivo rabbit heart model of AF.
Compound 8b was effective in treating doxorubicin-induced heart failure in mice, a condition in which dronedarone shows no therapeutic benefit.
Atrial fibrillation is a common heart rhythm disorder. The drug dronedarone is used to treat it, but it can cause side effects such as slowed electrical conduction in the heart (conduction block) and an overly long QT interval, which is a risk marker for dangerous rhythm problems. The researchers designed new compounds that block two kinds of ion flow in heart cells: the potassium current IKr and the late sodium current. They did not want them to block the main (peak) sodium current, which dronedarone does. The lead compound, 8b, blocked IKr about as strongly as dronedarone did (IC50 1.5 μM). It also blocked the late sodium current (IC50 2.5 μM) without inhibiting the peak sodium current. The intent is that blocking the late sodium current would offset excessive QT prolongation and avoid conduction block. In mice, 8b was absorbed well when given by mouth and had a half-life of about 5 hours. It was also selective for its target ion channels. In an isolated rabbit heart model of atrial fibrillation, it showed antiarrhythmic effects. It was also effective in mice with doxorubicin-induced heart failure, where dronedarone shows no benefit. This research suggests that 8b could be a candidate for a new class III antiarrhythmic drug. The findings come from lab, animal, and isolated-heart experiments, so they do not show whether the compound would be safe or effective in people.
Liao W, Wang W, Zhang A, Li B, Wang X, Tian C, et al.. (2026). 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.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c02024