Human Electrophysiological and Pharmacological Properties of XEN-D0101: A Novel Atrial Selective Kv1.5/IKur Inhibitor.

Ford, John and Milnes, James and Wettwer, Erich and Christ, Torsten and Rogers, Marc and Sutton, Kathy and Madge, David and Virág, László and Jost, Norbert and Horváth, Zoltán and Matschke, Klaus and Varró, András and Ravens, Ursula (2013) Human Electrophysiological and Pharmacological Properties of XEN-D0101: A Novel Atrial Selective Kv1.5/IKur Inhibitor. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 61 (5). pp. 408-415. ISSN 0160-2446

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Abstract

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 muM; hERG, 13 muM; activated-Nav1.5, >100 muM; inactivated-Nav1.5, 34 muM; Kir3.1/3.4, 17 muM; Kir2.1, >>100 muM). In atrial myocytes from patients in sinus rhythm (SR) and chronic atrial fibrillation (AF), XEN-D0101 inhibited non-inactivating outward currents (Ilate) with IC50 of 410 nM and 280 nM, respectively and peak outward currents (Ipeak) with IC50 of 806 nM and 240 nM, respectively. Whilst 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 (IC50 3.5 microM in SR and 1 microM in AF). Thus inhibition of Ipeak is due to 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 tissue) whilst 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. Conclusions: XEN-D0101 is a Kv1.5/IKur inhibitor with an attractive atrial-selective profile.

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