Blocking characteristics of hKv1.5 and hKv4.3/hKChIP2.2 after administration of the novel antiarrhythmic compound AZD7009

AZD7009 is a novel antiarrhythmic compound in early clinical development for management of atria] fibrillation. Electrophysiological studies in animals have shown high antiarrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. AZD7009 has previously been shown to inhibit hERG and hNav1.5 currents. The main objective of the present study was to characterize the effects of AZD7009 on hKv1.5 and hKv4.3/hKChIP2.2 currents to get a deeper understanding of the ion channel-blocking properties of the compound. hKv1.5 and hKv4.3/hKChIP2.2 currents were expressed in CHO cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited hKv1.5 and hKv4.3/hKChIP2.2 currents with equal potency: the IC50 for hKv(1.5) block was 27.0 +/- 1.6 mu M (n = 6), and the IC50 for hKv4.3/hKChIP2.2 block was 23.7 +/- 4.4 mu M (n = 5). Block of the hKv4.3/hKChIP2.2 current was frequency dependent with larger block at higher frequency, whereas block of the hKv1.5 current was slightly decreased at higher frequency. In conclusion, AZD7009 inhibits both the hKv1.5 and the hKv4.3/hKChIP2.2 currents. These effects likely contribute to the effects described in animals in vivo.