Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting Na_V1.5, K_V1.5, and K₂P...

Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as Na_V1.5, K_V1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed as multi-target inhibitors of these ion channels to address AF. Compound 6f emerged as the most potent in the series, demonstrating a strong inhibition of TASK-1 (IC₅₀ ∼ 0.3 μM), a moderate inhibition of Na_V1.5 (IC₅₀ ∼ 21.2 μM) and a subtle inhibition of K_V1.5 (IC₅₀ ∼ 81.5 μM), alongside unexpected activation of TASK-4 (∼ 40% at 100 μM). Functional assays on human atrial cardiomyocytes from sinus rhythm (SR) and patients with AF revealed that 6f reduced action potential amplitude in SR (indicating Na_V1.5 block), while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, 6f caused hyperpolarization of the resting membrane potential in AF cardiomyocytes, consistent with the observed TASK-4 activation. Mathematical modeling further validated its efficacy in reducing AF burden. Pharmacokinetic analyses suggest favorable absorption and low toxicity. These findings identify 6f as a promising multi-target therapeutic candidate for AF management.