Human electrophysiological and pharmacological properties of XEN-D0101: a novel atrial-selective Kv1.5/IKur inhibitor.
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.
Xention Ltd, Iconix Park, Pampisford, Cambridge, UK. john.ford@xention.com
John
J
Ford
James
J
Milnes
Erich
E
Wettwer
Torsten
T
Christ
Marc
M
Rogers
Kathy
K
Sutton
David
D
Madge
Laszlo
L
Virag
Norbert
N
Jost
Zoltan
Z
Horvath
Klaus
K
Matschke
Andras
A
Varro
Ursula
U
Ravens
D000200:Action Potentials / Q000502:physiology*; D001281:Atrial Fibrillation / Q000188:drug therapy; D016275:Atrial Function / Q000187:drug effects*; D002460:Cell Line; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D016276:Ventricular Function / Q000502:physiology*
D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D011743:Pyrimidines; D013876:Thiophenes; C584128:XEN-D0101; D011188:Potassium