RT Journal Article SR Electronic T1 Pharmacological Characterization of Abediterol, a Novel Inhaled β2-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 497 OP 509 DO 10.1124/jpet.112.193284 VO 342 IS 2 A1 Aparici, Mònica A1 Gómez-Angelats, Mireia A1 Vilella, Dolors A1 Otal, Raquel A1 Carcasona, Carla A1 Viñals, Marisa A1 Ramos, Israel A1 Gavaldà, Amadeu A1 De Alba, Jorge A1 Gras, Jordi A1 Cortijo, Julio A1 Morcillo, Esteban A1 Puig, Carlos A1 Ryder, Hamish A1 Beleta, Jorge A1 Miralpeix, Montserrat YR 2012 UL http://jpet.aspetjournals.org/content/342/2/497.abstract AB Abediterol is a novel potent, long-acting inhaled β2-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human β2-adrenoceptor and a functional selectivity over β1-adrenoceptors higher than that of formoterol and indacaterol in both a cellular model with overexpressed human receptors and isolated guinea pig tissue. Abediterol is a full agonist at the human β2-adrenoceptor (Emax = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC50 = 1.9 ± 0.4 nM; t½ onset = 7–10 min) is not significantly different from that of formoterol, but its duration of action (t½ ∼ 690 min) is similar to that of indacaterol. Nebulized abediterol inhibits acetylcholine-induced bronchoconstriction in guinea pigs in a concentration-dependent manner, with higher potency and longer duration of action (t½ = 36 h) than salmeterol (t½ = 6 h) and formoterol (t½ = 4 h) and similar duration of action to indacaterol up to 48 h. In dogs, the bronchoprotective effect of abediterol is more sustained than that of salmeterol and indacaterol at doses without effects on heart rate, thus showing a greater safety margin (defined as the ratio of dose increasing heart rate by 5% and dose inhibiting bronchospasm by 50%) than salmeterol, formoterol, and indacaterol (5.6 versus 3.3, 2.2, and 0.3, respectively). In conclusion, our results suggest that abediterol has a preclinical profile for once-daily dosing in humans together with a fast onset of action and a favorable cardiovascular safety profile.