Blocking characteristics of hERG, hNav1.5, and hKvLQT1/hminK after administration of the novel anti-arrhythmic compound AZD7009.
BACKGROUND
AZD7009 is a novel anti-arrhythmic compound under development for short- and long-term management of atrial fibrillation and flutter. Electrophysiological studies in animals have shown high anti-arrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. The main aim of this study was to characterize the blocking effects of AZD7009 on the human ether-a-go-go-related gene (hERG), the hNav1.5, and the hKvLQT1/hminK currents.


RESULTS
hERG, hKvLQT1/hminK, and hNav1.5 were expressed in CHO K1 cells. Currents were measured using the whole-cell configuration of the voltage-clamp technique. AZD7009 inhibited the hERG current with an IC50 of 0.6 +/- 0.07 microM (n = 6). AZD7009 1 microM hyperpolarized the potential for half-maximal activation from -8.2 +/- 0.1 mV to -18.0 +/- 0.6 mV (P < 0.001, n = 14) and induced pre-pulse potentiation at potentials near the activation threshold. The hNav1.5 current was blocked with an IC50 of 4.3 +/- 1.20 microM at 10 Hz (n = 6) and block developed use-dependently. Recovery from use-dependent block was slow, tau= 131 seconds. AZD7009 inhibited the hKvLQT1/hminK current only at high concentrations (IC50= 193 +/- 20 microM, n = 6).


CONCLUSIONS
AZD7009 inhibits both the hERG and the hNav1.5 current, and it is most likely this combined current block that underlies the prolongation of the refractoriness and the low proarrhythmic activity demonstrated in animals in vivo.
Persson
Frida
F
AstraZeneca R&D Mölndal, Mölndal, Sweden.
Carlsson
Leif
L
Duker
Göran
G
Jacobson
Ingemar
I
D000200:Action Potentials / Q000187:drug effects*; D000889:Anti-Arrhythmia Agents / Q000378:metabolism / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000188:drug therapy; D027682:Cation Transport Proteins / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects*; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects*; D026941:Sodium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000187:drug effects*; D000071230:Transcriptional Regulator ERG
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG