AZD3199: A potent and selective β2-adrenergic receptor agonist with rapid onset of action

Background: β2-agonists are standard treatments for asthma and COPD and are varyingly optimized for a number of key pharmacological properties, such as receptor selectivity, systemic exposure, onset of action and duration of effect. AZD3199 is a novel ultra long acting β2-agonist (uLABA) with improved properties designed to combine 24 hour duration of effect with low systemic exposure and an onset of action similarly rapid to that of formoterol. Methods: The affinity, potency and efficacy of AZD3199 were measured at human β-adrenergic receptors. Onset of action was measured as relaxation of constricted guinea pig trachea and human bronchial tissue. Activity at the hERG voltage-dependent potassium channel was determined using electrophysiology. Plasma protein binding was measured in multiple species. Results: AZD3199 was a potent agonist (6 nM EC50) at the human β2 receptor with an intrinsic activity of 0.8 relative to formoterol. AZD3199 had a rapid onset of action in both guinea pig (22 min) and human (11 min) lung tissue, very similar to formoterol (G-Pig 23 min, human 13 min) and significantly faster than salmeterol (>100 min in both). Similar β2-agonist activity was seen across multiple species including guinea pig, rat, dog, mouse and rabbit. AZD3199 was highly selective (>1500 fold affinity) for the human β2 receptor over human β1 and β3- receptors with no agonism at either receptor. No activity was seen at the hERG channel at concentrations up to 26 μM. High plasma protein binding (>90%) was seen across multiple species offering the potential for reduced systemic exposure. Conclusion: AZD3199 is a potent and selective uLABA with an onset of action similar to that of formoterol.