Abediterol (LAS100977), an inhaled long-acting β2-adrenoceptor agonist, has a fast association rate and long residence time at receptor

Abstract

This study describes the association rate and residence time of abediterol, a novel long-acting β2-adrenoceptor agonist (LABA) in Phase II development for treatment of asthma and COPD, in comparison with indacaterol, olodaterol, vilanterol and salmeterol, for both human β1- and β2-adrenoceptors.Abediterol association and dissociation rates were monitored directly by using its tritiated form. Moreover, association was determined indirectly using experimental Ki and koff obtained from assays performed with unlabelled compound. Dissociation was also studied indirectly by measuring the association rate of 3H-CGP12177 to beta adrenoceptors previously occupied by unlabelled compounds.Abediterol shows a fast association for the β2-adrenoceptor (kon 1.4 × 107 ± 1.8 × 106M−1min−1) while its dissociation rate is between 30 and 64 times slower than that of the reference LABA compounds tested, with a residence time of 91.3 ± 13.3min (measured directly) and 185.5 ± 7.5min (measured indirectly). Abediterol shows kinetic selectivity for the β2- over the β1-adrenoceptor, with a dissociation rate from the β1-adrenoceptor similar to the other LABA compounds tested.In conclusion, abediterol is a potent LABA with a fast association rate and a long residence time at β2-adrenoceptors. These data are in agreement with the onset and duration of action of abediterol shown in humans.