Abstract
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.
Footnotes
This work was supported by Almirall SA, Barcelona, Spain; the Ministry of Science and Innovation, Spanish Government [Grants SAF2008-03113 (to J.C.), SAF2009-08913 (to E.J.M.)]; European Funds for Regional Development; Centro de Investigación en Red de Enfermedades Respiratorias, Health Institute Carlos III (Spanish Government) [Grant CB06/06/0027]; the Consorcios Estratégicos Nacionales de Investigación Tecnológica Programme (Genius Pharma; Spanish Government); and Regional Government (Generalitat Valenciana) [Grant Prometeu 2008/045].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- COPD
- chronic obstructive pulmonary disease
- Ach
- acetylcholine
- ANOVA
- analysis of variance
- CHO
- Chinese hamster ovary
- CI
- confidence interval
- CRC
- concentration-response curve
- ED5
- dose increasing heart rate by 5%
- EFS
- electrical field stimulation
- IBMX
- 3-isobutyl-1-methylxanthine
- LABA
- long-acting β-adrenergic agonist
- PSS
- physiological salt solution
- SABA
- short-acting β-agonist
- CGP12177
- 4-[3-(tert-butylamino)-2-hydroxypropoxy]-1,3-dihydrobenzimidazol-2-one
- CGP20712A
- 1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol methanesulfonate
- ZD7114
- (S)-4-[2-hydroxy-3-phenoxypropylaminoethoxy]-N-(2-methoxyethyl)phenoxyacetamide
- ICI-118551
- (±)-erythro-(S*,S*)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride.
- Received March 1, 2012.
- Accepted May 14, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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