AZD2927
Preclinical pharmacology and pharmacokinetics
AZD2927 selectively blocks acetylcholine-regulated inwardly rectifying potassium current (IKACh) in human atrial myocytes (IC50=0.35 µM) 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 with AZD2927 in anaesthetised male NZW rabbit 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.
Mechanism of Action
Acetylcholine-regulated inwardly rectifying potassium current (IKACh) blocker
Original Therapeutic Area
Cardiovascular, Renal and Metabolism
CNS Penetrant
Low
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Walfridsson H., et al. (2014).
Is the acetylcholine-regulated inwardly rectifying potassium current a viable antiarrhythmic target? Translational discrepancies of AZD2927 and A7071 in dogs and humans. Europace. 2015 Mar;17(3):473-82. doi: 10.1093/europace/euu192. Epub 2014 Jul 31. PMID: 25082948.