Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation

Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as Na<sub>V</sub>1.5, K<sub>V</sub>1.5, 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 (IC<sub>50</sub> ∼ 0.3 μM), a moderate inhibition of Na<sub>V</sub>1.5 (IC<sub>50</sub> ∼ 21.2 μM) and a subtle inhibition of K<sub>V</sub>1.5 (IC<sub>50</sub> ∼ 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<sub>V</sub>1.5 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.

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Publication Details

Journal
Journal of Biological Chemistry
Published
2025-03-05
DOI
https://doi.org/10.1016/j.jbc.2025.108387
Citations
2
Primary Topic
Computational Drug Discovery Methods
Type
article
Field-Weighted Citation Impact
3.01

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article

Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation

Alfonso Bueno‐Orovio, Wendy González, José Carlos Estanislao Márquez Montesinos, Francisco Adasme‐Carreño et al.
2 citations
Journal of Biological Chemistry
Computational Drug Discovery Methods
3.01
article

Rational design, synthesis, and evaluation of novel polypharmacological compounds targeting NaV1.5, KV1.5, and K2P channels for atrial fibrillation

Alfonso Bueno‐Orovio, Wendy González, José Carlos Estanislao Márquez Montesinos, Francisco Adasme‐Carreño, Diego Varela, Whitney Venturini, Constanze Schmidt, Aytuğ K. Kiper, Paula Andrea Peña-Martínez, Yuliet Mazola, Lorena Camargo-Ayala, Albert Dasí, Luis Prent-Peñaloza, Paola Andrea Camargo-Ayala, Leandro Zúñiga, Sven Schütte, Ursula Ravens, Margarita Gutiérrez, Felix Wiedmann, Mauricio Bedoya, Merten Prüser, Blanca Rodríguez, Niels Decher, Susanne Rinné, Rafael Zúñiga
article en
2 citations

Abstract

Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as Na<sub>V</sub>1.5, K<sub>V</sub>1.5, 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 (IC<sub>50</sub> ∼ 0.3 μM), a moderate inhibition of Na<sub>V</sub>1.5 (IC<sub>50</sub> ∼ 21.2 μM) and a subtle inhibition of K<sub>V</sub>1.5 (IC<sub>50</sub> ∼ 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<sub>V</sub>1.5 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.

Journal of Biological ChemistryVol. 301(4)
University of Talca (CL), Universidad Andrés Bello (CL), Philipps University of Marburg (DE), Heidelberg University (DE), Universitätsmedizin Greifswald (DE), Catholic University of the Maule (CL), University Medical Center Freiburg (DE), Universidad Autónoma de Chile (CL), British Heart Foundation (GB), Universität Greifswald (DE), University of Oxford (GB), Millennium Nucleus of Ion Channel Associated Diseases (CL), Universitäts-Herzzentrum Freiburg-Bad Krozingen (DE), Heidelberg University (US)
Wellcome Trust, Deutsches Zentrum für Herz-Kreislaufforschung, UK Research and Innovation, Deutsche Forschungsgemeinschaft, Else Kröner-Fresenius-Stiftung, Deutsche Herzstiftung, Universidad de Talca, Agencia Nacional de Investigación y Desarrollo, Engineering and Physical Sciences Research Council, Fondo de Innovación para la Competitividad
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Openalex Percentile: Top 10%
Computational Drug Discovery Methods
3.01
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