Human Electrophysiological and Pharmacological Properties of XEN-D0101: A Novel Atrial-Selective Kv1.5/IKur Inhibitor
Open accessAbstract
The human electrophysiological and pharmacological properties of XEN-D0101 were evaluated to assess its usefulness for treating atrial fibrillation (AF). XEN-D0101 inhibited Kv1.5 with an IC50 of 241 nM and is selective over non-target cardiac ion channels (IC50 Kv4.3, 4.2 μM; hERG, 13 μM; activated Nav1.5, >100 μM; inactivated Nav1.5, 34 μM; Kir3.1/3.4, 17 μM; Kir2.1, >>100 μM). In atrial myocytes from patients in sinus rhythm (SR) and chronic AF, XEN-D0101 inhibited non-inactivating outward currents (Ilate) with IC50 of 410 and 280 nM, respectively, and peak outward currents (Ipeak) with IC50 of 806 and 240 nM, respectively. Whereas Ilate is mainly composed of IKur, Ipeak consists of IKur and Ito. Therefore, the effects on Ito alone were estimated from a double-pulse protocol where IKur was inactivated (3.5 µM IC50 in SR and 1 µM in AF). Thus, inhibition of Ipeak is because of IKur reduction and not Ito. XEN-D0101 significantly prolonged the atrial action potential duration at 20%, 50%, and 90% of repolarization (AF tissue only) and significantly elevated the atrial action potential plateau phase and increased contractility (SR and AF tissues) while having no effect on human ventricular action potentials. In healthy volunteers, XEN-D0101 did not significantly increase baseline- and placebo-adjusted QTc up to a maximum oral dose of 300 mg. XEN-D0101 is a Kv1.5/IKur inhibitor with an attractive atrial-selective profile.
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Several compounds that inhibit the ultrarapid potassium current (IKur) and other inhibitors of atypical ion channels are in clinical development.
“Several compounds that inhibit the ultrarapid potassium current (I Kur ) and other inhibitors of atypical ion channels are in clinical development.[673][674][675]”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [674]
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- Authors
- Ford, J., Milnes, J., Wettwer, E., Christ, T., Rogers, M., Sutton, K., Madge, D., Virag, L., Jost, N., Horvath, Z., Matschke, K., Varro, A., & Ravens, U.
- Affiliations
- Xention (United Kingdom) (GB)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Szeged (HU)
- Herzzentrum Dresden Universitätsklinik (DE)
- Corresponding author
- Ford, John
- Milnes, James
- Rogers, Marc
- Sutton, Kathy
- Madge, David
- Venue
- Journal of Cardiovascular Pharmacology
- Published
- 2013-05
- Volume
- 61
- Issue
- 5
- Pages
- 408-415
- ISSN
- 0160-2446 (ISSN-L)
- OpenAlex
- W2066509395
- Cited by
- 62
- References
- 20
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 8 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 6 · 2015: 8 · 2014: 8 · 2013: 5
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- Locations
- Journal of Cardiovascular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
- Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- European Commission (261057)
- Hungarian Scientific Research Fund (OTKA CNK-77855, OTKA K-82079)
- Nemzeti Kutatási és Technológiai Hivatal (NKFP_07_01-RYT07_AF)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- Kv1.5, IKur, atrial fibrillation, antiarrhythmic drugs, atrial myocytes, action potential duration, hERG, cardiac sodium channel, inwardly rectifying potassium channels, QTc prolongation, atrial contractility
- MeSH terms
- Action Potentials, Atrial Fibrillation, Cell Line, Double-Blind Method, Electrocardiography, Heart Atria, Humans, Male, Myocardial Contraction, Potassium, Pyrimidines, Thiophenes, Atrial Function, Ventricular Function, Potassium Channel Blockers, Myocytes, Cardiac, Kv1.5 Potassium Channel, In Vitro Techniques
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