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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*Xention Ltd, Iconix Park, Pampisford, Cambridge, United Kingdom;
†Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany; T. Christ is now with the Institut für Experimentelle Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg;
‡Department of Pharmacology and Pharmacotherapy; and
§Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, University of Szeged, Szeged, Hungary; and
¶Department of Cardiac Surgery, Heart Center Dresden, Dresden University of Technology, Dresden, Germany.
Reprints: John Ford, PhD, Xention Ltd, Iconix Park, London Road, Pampisford, Cambridge CB22 3EG, United Kingdom (e-mail: email@example.com).
Supported by Xention Ltd, the National Development Agency (TÁMOP-4.2.2/B-10/1-2010-0012; the National Office for Research and Technology—National Technology Programmes (NKFP_07_01—RYT07_AF and REG-DA-09-2-2009-0115); EU FP7-Health-2010-single-stage "EUTRAF" (European Network for Translational Research in Atrial Fibrillation), #261057; the HU-RO Cross Border Cooperation Programmes (HURO/0802/011_AF-HURO_CARDIOPOL); and by the Hungarian Scientific Research Fund (OTKA K-82079 and OTKA CNK-77855).
J. Ford, D. Madge, K. Sutton, M. Rogers, and J. Milnes hold options in Xention Ltd. U. Ravens and E. Wettwer both consult to Xention Ltd.
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Received August 03, 2012
Accepted January 11, 2013