Characteristics of AZD9708, a novel, selective β2-adrenoceptor agonist with rapid onset and long duration of action.

Abstract Here we describe the pre-clinical pharmacological profile of AZD9708, a novel long-acting β 2 -adrenoceptor agonist that has potential as a once-daily therapy for asthma and chronic obstructive pulmonary disease (COPD). AZD9708 is a potent and selective agonist at the human β 2 -adrenoceptor, with selectivity over human β 1 - and β 3 -adrenoceptors of >500 and >24 fold, respectively. AZD9708 relaxes carbachol-induced contraction of human bronchial rings with a time to 90% of maximal relaxation of 13–20 min, similar to that seen with formoterol and quicker than salmeterol. In anesthetized guinea pigs, AZD9708 provides significant protection against histamine-induced airway constriction at 24 h after intratracheal and nebulized doses. This is longer than with intratracheal salmeterol, which is bronchoprotective for approximately 8 h, and formoterol, which is bronchoprotective for 8 and 12 h following nebulized and intratracheal dosing, respectively. AZD9708 also shows the potential for a greater therapeutic margin than widely used β 2 -adrenoceptor agonists such as formoterol. At a defined efficacy dose that provides 80% bronchoprotection (ED 80 ), formoterol leads to a decrease in blood potassium levels in guinea pigs, whilst AZD9708 is not associated with significant reductions in potassium levels at doses up to 7 times the ED 80 . [ 14 C]AZD9708 is associated with extensive protein binding in both human (mean 1.0% free) and rat (mean 2.6% free) plasma. This pharmacological profile indicates the potential of AZD9708 to become an important addition to the range of bronchodilators available for the treatment of patients with obstructive airways disease.