title: In vitro and in vivo preclinical profile of abediterol (LAS100977), an inhaled long-acting β2-adrenoceptor agonist, compared with indacaterol, olodaterol and vilanterol.
abstract: Abediterol is a novel long-acting β2-adrenoceptor agonist (LABA) currently in development for once-daily combination maintenance therapy of asthma and COPD. This study investigated the preclinical profile of abediterol in terms of affinity, potency, selectivity, duration of action and cardiac effects in comparison to the marketed once-daily LABAs indacaterol, olodaterol and vilanterol. Abediterol was the compound with the highest in vitro potency for dog, guinea pig and human β2-adrenoceptors. In electrical field stimulated guinea pig trachea, abediterol demonstrated 5-, 44- and 77-fold greater potency than olodaterol, indacaterol and vilanterol, respectively. In anaesthetised guinea pigs, inhaled abediterol was also the most potent compound, with 5-20 times higher bronchoprotective potency than other once-daily LABAs against acetylcholine. The bronchoprotective half-life of abediterol in guinea pigs was 36h compared with 51h for indacaterol, 47h for olodaterol, and 18h for vilanterol. In anaesthetised dogs, abediterol also inhibited acetylcholine-induced bronchoconstriction, with higher potency than olodaterol and vilanterol [ID40 (dose inhibiting bronchoconstriction by 40%) of 0.059µg/kg, 0.180µg/kg and 2.870µg/kg, respectively]. In parallel, effects on heart rate in dogs were also measured. Abediterol showed greater safety index (defined as the ratio of the maximal dose without effect on heart rate and the ID40) than olodaterol and vilanterol (10.5 versus 4.9 and 2.4, respectively). Taken together, these data suggest that abediterol offers potent bronchodilation and a sustained duration of action suited to once-daily dosing, plus a reduced potential for class-related cardiac side effects.
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain. Electronic address: monica.aparici@almirall.com.
authors.forename: Mònica
authors.initials: M
authors.lastname: Aparici
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Gavaldà
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Israel
authors.initials: I
authors.lastname: Ramos
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Carcasona
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Otal
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Joan Antoni
authors.initials: JA
authors.lastname: Fernández-Blanco
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Jose Luís
authors.initials: JL
authors.lastname: Montero
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Vicente Marco
authors.initials: VM
authors.lastname: García
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: López
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: De Alba
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Christopher
authors.initials: C
authors.lastname: Doe
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Puig
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Vilella
authors.affiliation: Almirall R&D Centre, Laureà Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Miralpeix
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D001592:Benzyl Alcohols / Q000494:pharmacology*; D002722:Chlorobenzenes / Q000494:pharmacology*; D004285:Dogs; D006168:Guinea Pigs; D007189:Indans / Q000494:pharmacology*; D008297:Male; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012449:Safety; D013997:Time Factors
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; D048588:Benzoxazines; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D007189:Indans; D015363:Quinolones; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; C550468:vilanterol; C510790:indacaterol; C549647:olodaterol
keywords: Abediterol (PubChem CID 11962616); CGP12177 (PubChem CID 2687); COPD; bronchodilator; indacaterol (PubChem CID 6918554); isoprenaline sulphate (PubChem CID 8239); long-acting β(2)-adrenoceptor agonist; olodaterol (PubChem CID 11504295); propranolol (PubChem CID 4946); vilanterol (PubChem CID 10184665).