title: Pharmacological characterization of abediterol, a novel inhaled β(2)-adrenoceptor agonist with long duration of action and a favorable safety profile in preclinical models.
abstract: Abediterol is a novel potent, long-acting inhaled β(2)-adrenoceptor agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Abediterol shows subnanomolar affinity for the human β(2)-adrenoceptor and a functional selectivity over β(1)-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 β(2)-adrenoceptor (E(max) = 91 ± 5% of the maximal effect of isoprenaline). The potency and onset of action that abediterol shows in isolated human bronchi (EC(50) = 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.
authors.affiliation: Almirall R&D Center, Sant Feliu de Llobregat, Barcelona, Spain. monica.aparici@almirall.com
authors.forename: Mònica
authors.initials: M
authors.lastname: Aparici
authors.forename: Mireia
authors.initials: M
authors.lastname: Gómez-Angelats
authors.forename: Dolors
authors.initials: D
authors.lastname: Vilella
authors.forename: Raquel
authors.initials: R
authors.lastname: Otal
authors.forename: Carla
authors.initials: C
authors.lastname: Carcasona
authors.forename: Marisa
authors.initials: M
authors.lastname: Viñals
authors.forename: Israel
authors.initials: I
authors.lastname: Ramos
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.forename: Jorge
authors.initials: J
authors.lastname: De Alba
authors.forename: Jordi
authors.initials: J
authors.lastname: Gras
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
authors.forename: Esteban
authors.initials: E
authors.lastname: Morcillo
authors.forename: Carlos
authors.initials: C
authors.lastname: Puig
authors.forename: Hamish
authors.initials: H
authors.lastname: Ryder
authors.forename: Jorge
authors.initials: J
authors.lastname: Beleta
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D015363:Quinolones / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D000068299:Salmeterol Xinafoate
chemical_list: C576952:5-(2-((6-(2,2-difluoro-2-phenylethoxy)hexyl)amino)-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D015363:Quinolones; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate