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Research ArticleDrug Discovery and Translational Medicine

Pharmacological Characterization of Abediterol, a Novel Inhaled β2-Adrenoceptor Agonist with Long Duration of Action and a Favorable Safety Profile in Preclinical Models

Mònica Aparici, Mireia Gómez-Angelats, Dolors Vilella, Raquel Otal, Carla Carcasona, Marisa Viñals, Israel Ramos, Amadeu Gavaldà, Jorge De Alba, Jordi Gras, Julio Cortijo, Esteban Morcillo, Carlos Puig, Hamish Ryder, Jorge Beleta and Montserrat Miralpeix
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 497-509; DOI: https://doi.org/10.1124/jpet.112.193284
Mònica Aparici
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Mireia Gómez-Angelats
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Dolors Vilella
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Raquel Otal
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Carla Carcasona
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Marisa Viñals
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Israel Ramos
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Amadeu Gavaldà
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Jorge De Alba
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Jordi Gras
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Julio Cortijo
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Esteban Morcillo
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Carlos Puig
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Hamish Ryder
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Jorge Beleta
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Montserrat Miralpeix
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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.

    http://dx.doi.org/10.1124/jpet.112.193284.

  • 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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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleDrug Discovery and Translational Medicine

In Vitro and In Vivo Characterization of Abediterol

Mònica Aparici, Mireia Gómez-Angelats, Dolors Vilella, Raquel Otal, Carla Carcasona, Marisa Viñals, Israel Ramos, Amadeu Gavaldà, Jorge De Alba, Jordi Gras, Julio Cortijo, Esteban Morcillo, Carlos Puig, Hamish Ryder, Jorge Beleta and Montserrat Miralpeix
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 497-509; DOI: https://doi.org/10.1124/jpet.112.193284

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Research ArticleDrug Discovery and Translational Medicine

In Vitro and In Vivo Characterization of Abediterol

Mònica Aparici, Mireia Gómez-Angelats, Dolors Vilella, Raquel Otal, Carla Carcasona, Marisa Viñals, Israel Ramos, Amadeu Gavaldà, Jorge De Alba, Jordi Gras, Julio Cortijo, Esteban Morcillo, Carlos Puig, Hamish Ryder, Jorge Beleta and Montserrat Miralpeix
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 497-509; DOI: https://doi.org/10.1124/jpet.112.193284
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