In vitro and in vivo preclinical profile of abediterol (LAS100977), an inhaled long-acting β₂-adrenoceptor agonist, compared with indacaterol, olodaterol and vilanterol

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• 作者：Mò ; nica Aparici ; ^{monica.aparici@almirall.com" class="auth_mail" title="E-mail the corresponding author} ; Amadeu Gavaldà ; Israel Ramos ; Carla Carcasona ; Raquel Otal ; Joan Antoni Ferná ; ndez-Blanco ; Jose Luí ; s Montero ; Vicente Marco Garcí ; a ; Rosa Ló ; pez ; Jorge De Alba ; Christopher Doe ; Carlos Puig ; Dolors Vilella ; Montserrat Miralpeix
• 关键词：ANOVA ; analysis of variance ; CGP12177 ; 4-(3-tert-butylamino-2-hydroxypropoxy)-benzimidazol-2-one hydrochloride ; COPD ; chronic obstructive pulmonary disease ; EFS ; electrical field stimulation ; EC50 ; concentration that induces 50% of the maximum effect ; Emax ; maximum effect ; FDA ; US Food and Drug Administration ; FEV1 ; forced expiratory volume in 1  ; s ; IC50 ; half maximal inhibitory concentration ; LABA ; long-acting β-adrenoceptor agonist
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 January 2016
• 年：2016
• 卷：770
• 期：Complete
• 页码：61-69
• 全文大小：683 K

文摘

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 36 h compared with 51 h for indacaterol, 47 h for olodaterol, and 18 h 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 0.059 µg/kg, 0.180 µg/kg and 2.870 µg/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.