Abediterol has higher β 2 -receptor affinity and in vitro bronchodilatory potency than other long-acting β 2 -agonists, with good selectivity

Introduction Abediterol (LAS100977) is a novel, long-acting, inhaled ß 2 -receptor agonist in Phase II development for asthma and COPD. We report the in vitro potency, selectivity and duration of action (DoA) of abediterol vs indacaterol, olodaterol and vilanterol. Methods Affinity studies used chinese hamster ovary cells expressing human, guinea pig (GP) or dog β 1 or β 2 receptors. Potency, onset and DoA were assessed in vitro in GP trachea. Onset (time to 50% maximal relaxation) and DoA (time to 50% recovery of maximal contraction) were assessed at IC 80 concentration. β 1 -receptor activity was assessed in GP left heart atria at cumulative concentrations (1 nM–10 μM). Results Abediterol had the highest ß 2 -receptor affinity vs comparators; all compounds had substantially lower ß 1 -receptor affinity (Table). The potency of abediterol (0.1 nM) was 5-, 77- and 80-fold greater than olodaterol, indacaterol and vilanterol, respectively. Abediterol had slightly slower onset vs comparators. DoA of abediterol was similar to vilanterol (both >480 min) and longer than indacaterol (218 min) and olodaterol (325 min). Abediterol, olodaterol and vilanterol all had very low potency in atrial tissue (EC 50 >10 μM), vs 6.3 μM for indacaterol. Conclusion Abediterol is a potent ß 2 -receptor agonist with a long DoA in tracheal tissue and low activity in atrial tissue, suggesting that abediterol may offer reduced potential for cardiac effects in humans. Receptor affinity IC 50 (nM) Guinea pig Dog Human ß 1 ß 2 ß 1 ß 2 ß 1 ß 2 Abediterol 136 0.4 135 0.4 36 0.6 Indacaterol 542 4.6 339 7.8 136 34 Olodaterol 635 1.4 705 1.7 133 4.2 Vilanterol 2485 1.1 2445 3.0 1800 7.4