Xention Ltd, Iconix Park, Pampisford, Cambridge, UK.
J Cardiovasc Pharmacol. 2013 May;61(5):408-15. doi: 10.1097/FJC.0b013e31828780eb.
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.
XEN-D0101 的人体电生理和药理学特性已被评估，以评估其在治疗心房颤动 (AF) 中的有用性。XEN-D0101 以 241 nM 的 IC50 抑制 Kv1.5，对非靶向心脏离子通道具有选择性（IC50 Kv4.3，4.2 μM；hERG，13 μM；激活的 Nav1.5，>100 μM；失活的 Nav1.5，34 μM；Kir3.1/3.4，17 μM；Kir2.1，>>100 μM）。在窦性节律 (SR) 和慢性 AF 患者的心房肌细胞中，XEN-D0101 分别以 410 和 280 nM 的 IC50 抑制非失活外向电流 (Ilate)，并以 806 和 240 nM 的 IC50 抑制峰值外向电流 (Ipeak)。虽然 Ilate 主要由 IKur 组成，但 Ipeak 由 IKur 和 Ito 组成。因此，从 IKur 失活的双脉冲方案中估计 Ito 单独的作用（SR 中的 3.5 µM IC50 和 AF 中的 1 µM）。因此，Ipeak 的抑制是由于 IKur 减少而不是 Ito。XEN-D0101 显著延长心房动作电位复极化 20%、50%和 90%时的持续时间（仅在 AF 组织中），显著升高心房动作电位平台期并增加收缩力（SR 和 AF 组织），而对人心室动作电位没有影响。在健康志愿者中，XEN-D0101 最高口服剂量为 300 mg 时，基线和安慰剂校正后的 QTc 无明显增加。XEN-D0101 是一种 Kv1.5/IKur 抑制剂，具有有吸引力的心房选择性特征。
