Mechanism of action: Acetylcholine-regulated inwardly rectifying potassium current (IKACh) blocker
AZD2927 selectively blocks IKACh in human atrial myocytes (IC50=0.35µM) and in CHO cells expressing the human isoform of the channel protein (Kir3.1/Kir3.4, IC50=1.3µM) with minimal off-target activity. AZD2927 has limited CNS exposure in rats and so is thought to be restricted to the periphery. Efficacy was demonstrated in anaesthetised male NZW rabbit with AZD2927 producing a 20ms increase in the right atrial effective refractory period at a predicted unbound plasma concentration of 0.5µM. Similarly, in anaesthetised beagle dog a 20ms increase was observed at a predicted 0.2µM compound concentration. Antiarrhythmic efficacy was demonstrated in a dog disease model of rapid pacing-induced atrial fibrillation (AF) both in terms of restoring sinus rhythm and inhibiting induction of AF. AZD2927 was used as a tool compound for a Proof of Principle study in patients with atrial flutter but efficacy was not demonstrated at the dose tested.