Human Electrophysiological and Pharmacological Properties of XEN-D0101

A Novel Atrial-Selective Kv1.5/I_Kur 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 (I_late) with IC₅₀ of 410 and 280 nM, respectively, and peak outward currents (I_peak) with IC₅₀ of 806 and 240 nM, respectively. Whereas I_late is mainly composed of I_Kur, I_peak consists of I_Kur and I_to. Therefore, the effects on I_to alone were estimated from a double-pulse protocol where I_Kur was inactivated (3.5 µM IC₅₀ in SR and 1 µM in AF). Thus, inhibition of I_peak is because of I_Kur reduction and not I_to. 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/I_Kur inhibitor with an attractive atrial-selective profile.