RESUMEN
This study describes the association rate and residence time of abediterol, a novel long-acting ß2-adrenoceptor agonist (LABA) in Phase II development for treatment of asthma and COPD, in comparison with indacaterol, olodaterol, vilanterol and salmeterol, for both human ß1- and ß2-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 ß2-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 ß2- over the ß1-adrenoceptor, with a dissociation rate from the ß1-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 ß2-adrenoceptors. These data are in agreement with the onset and duration of action of abediterol shown in humans.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Quinolonas/metabolismo , Quinolonas/farmacología , Receptores Adrenérgicos beta 2/metabolismo , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Humanos , Cinética , Quinolonas/administración & dosificación , Receptores Adrenérgicos beta 1/metabolismo , Especificidad por SustratoRESUMEN
Novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides have been identified as potent M3 muscarinic antagonists with a long duration of action in an in vivo model of bronchoconstriction. The synthesis, structure-activity relationships and biological evaluation of this series of compounds are reported.
Asunto(s)
Amidas/química , Antagonistas Muscarínicos/química , Compuestos de Amonio Cuaternario/química , Quinuclidinas/química , Receptor Muscarínico M3/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Sitios de Unión , Broncoconstrictores/síntesis química , Broncoconstrictores/química , Broncoconstrictores/farmacocinética , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Antagonistas Muscarínicos/síntesis química , Antagonistas Muscarínicos/farmacocinética , Unión Proteica , Estructura Terciaria de Proteína , Ratas , Receptor Muscarínico M3/metabolismo , Relación Estructura-ActividadRESUMEN
Novel quaternary ammonium derivatives of N,N-disubstituted (3R)-quinuclidinyl carbamates have been identified as potent M(3) muscarinic antagonists with long duration of action in an in vivo model of bronchoconstriction. These compounds have also presented a high level of metabolic transformation (human liver microsomes). The synthesis, structure-activity relationships and biological evaluation of these compounds are reported.
