Polypharmacological Modulation of Atrial Fibrillation: Rational Design, Synthesis, and Evaluation of Novel Compounds Targeting NaV1.5, KV1.5, and K2P Channels

During atrial fibrillation (AF), electrical remodeling occurs, involving ion channels like NaV1.5, KV1.5, and TASK-1. A promising AF treatment encompasses inhibiting these channels. In this study, acetamide compounds were designed based on the local anesthetic pharmacophore as potential NaV1.5, KV1.5, and TASK-1 inhibitors. Compound 6f emerged as the most potent in the series, with IC50 values determined in Xenopus oocytes of approximately 0.3 µM in TASK-1, 81.5 µM in KV1.5, and 21.2 µM in NaV1.5. Unexpectedly, 6f activated at 100 µM another cardiac K2P channel (TASK-4) by about 40%. Next, we performed patch clamp experiments of human atrial cardiomyocytes from sinus rhythm (SR) or AF patients. In SR 6f reduced action potential amplitude (indicating NaV1.5 block) while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, a hyperpolarization in resting membrane potential occurred in AF cardiomyocytes by 6f, consistent with the TASK-4 activation we observed. In a mathematical whole-atria model, 6f prolonged APD and tissue refractoriness, proving efficacious both for AF prevention and cardioversion. Favorable pharmacokinetic properties of 6f in silico, including good absorption and low toxicity, as well as its lack of cytotoxicity in a hemolytic assay, suggest its potential as an AF treatment.