RT Journal Article
SR Electronic
T1 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
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 Mònica Aparici
A1 Mireia Gómez-Angelats
A1 Dolors Vilella
A1 Raquel Otal
A1 Carla Carcasona
A1 Marisa Viñals
A1 Israel Ramos
A1 Amadeu Gavaldà
A1 Jorge De Alba
A1 Jordi Gras
A1 Julio Cortijo
A1 Esteban Morcillo
A1 Carlos Puig
A1 Hamish Ryder
A1 Jorge Beleta
A1 Montserrat Miralpeix
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.