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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, Vol. 61, No. 5, 01.05.2013, p. 408-15.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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 2013, 'Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor', J CARDIOVASC PHARM, vol. 61, no. 5, pp. 408-15. https://doi.org/10.1097/FJC.0b013e31828780eb

APA

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. (2013). Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. J CARDIOVASC PHARM, 61(5), 408-15. https://doi.org/10.1097/FJC.0b013e31828780eb

Vancouver

Ford J, Milnes J, Wettwer E, Christ T, Rogers M, Sutton K et al. Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor. J CARDIOVASC PHARM. 2013 May 1;61(5):408-15. https://doi.org/10.1097/FJC.0b013e31828780eb

Bibtex

@article{9e9f244ecff6410c8d7c3943c5a0951b,
title = "Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor",
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 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.",
keywords = "Action Potentials, Atrial Fibrillation, Atrial Function, Cell Line, Double-Blind Method, Electrocardiography, Heart Atria, Humans, Kv1.5 Potassium Channel, Male, Myocardial Contraction, Myocytes, Cardiac, Potassium, Potassium Channel Blockers, Pyrimidines, Thiophenes, Ventricular Function",
author = "John Ford and James Milnes and Erich Wettwer and Torsten Christ and Marc Rogers and Kathy Sutton and David Madge and Laszlo Virag and Norbert Jost and Zoltan Horvath and Klaus Matschke and Andras Varro and Ursula Ravens",
note = "Christ f{\"u}r: Tech Univ Dresden, Med Fac Carl Gustav Carus, Dept Pharmacol & Toxicol, Dresden, Germany",
year = "2013",
month = may,
day = "1",
doi = "10.1097/FJC.0b013e31828780eb",
language = "English",
volume = "61",
pages = "408--15",
journal = "J CARDIOVASC PHARM",
issn = "0160-2446",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

RIS

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 -