PT  - JOURNAL ARTICLE
AU  - Mònica Aparici
AU  - Mireia Gómez-Angelats
AU  - Dolors Vilella
AU  - Raquel Otal
AU  - Carla Carcasona
AU  - Marisa Viñals
AU  - Israel Ramos
AU  - Amadeu Gavaldà
AU  - Jorge De Alba
AU  - Jordi Gras
AU  - Julio Cortijo
AU  - Esteban Morcillo
AU  - Carlos Puig
AU  - Hamish Ryder
AU  - Jorge Beleta
AU  - Montserrat Miralpeix
TI  - Pharmacological Characterization of Abediterol, a Novel Inhaled β<sub>2</sub>-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models
AID  - 10.1124/jpet.112.193284
DP  - 2012 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 497--509
VI  - 342
IP  - 2
4099  - http://jpet.aspetjournals.org/content/342/2/497.short
4100  - http://jpet.aspetjournals.org/content/342/2/497.full
SO  - J Pharmacol Exp Ther2012 Aug 01; 342
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.