Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor
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Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. / Ford, John; Milnes, James; Wettwer, Erich; Christ, Torsten; Rogers, Marc; Sutton, Kathy; Madge, David; Virag, Laszlo; Jost, Norbert; Horvath, Zoltan; Matschke, Klaus; Varro, Andras; Ravens, Ursula.
in: J CARDIOVASC PHARM, Jahrgang 61, Nr. 5, 01.05.2013, S. 408-15.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor
AU - Ford, John
AU - Milnes, James
AU - Wettwer, Erich
AU - Christ, Torsten
AU - Rogers, Marc
AU - Sutton, Kathy
AU - Madge, David
AU - Virag, Laszlo
AU - Jost, Norbert
AU - Horvath, Zoltan
AU - Matschke, Klaus
AU - Varro, Andras
AU - Ravens, Ursula
N1 - Christ für: Tech Univ Dresden, Med Fac Carl Gustav Carus, Dept Pharmacol & Toxicol, Dresden, Germany
PY - 2013/5/1
Y1 - 2013/5/1
N2 - 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.
AB - 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.
KW - Action Potentials
KW - Atrial Fibrillation
KW - Atrial Function
KW - Cell Line
KW - Double-Blind Method
KW - Electrocardiography
KW - Heart Atria
KW - Humans
KW - Kv1.5 Potassium Channel
KW - Male
KW - Myocardial Contraction
KW - Myocytes, Cardiac
KW - Potassium
KW - Potassium Channel Blockers
KW - Pyrimidines
KW - Thiophenes
KW - Ventricular Function
U2 - 10.1097/FJC.0b013e31828780eb
DO - 10.1097/FJC.0b013e31828780eb
M3 - SCORING: Journal article
C2 - 23364608
VL - 61
SP - 408
EP - 415
JO - J CARDIOVASC PHARM
JF - J CARDIOVASC PHARM
SN - 0160-2446
IS - 5
ER -