The design of a novel series of muscarinic receptor antagonists leading to AZD8683, a potential inhaled treatment for COPD.
Bioorg Med Chem Lett
; 23(23): 6248-53, 2013 Dec 01.
Article
en En
| MEDLINE
| ID: mdl-24144851
ABSTRACT
A novel series of muscarinic receptor antagonists was developed, with the aim of identifying a compound with high M3 receptor potency and a reduced risk of dose-limiting side effects with potential for the treatment of COPD. Initial compound modifications led to a novel cycloheptyl series, which was improved by focusing on a quinuclidine sub-series. A wide range of N-substituents was evaluated to determine the optimal substituent providing a high M3 receptor potency, high intrinsic clearance and high human plasma protein binding. Compounds achieving in vitro study criteria were selected for in vivo evaluation. Pharmacokinetic half-lives, inhibition of bronchoconstriction and duration of action, as well as systemic side effects, induced by the compounds were assessed in guinea-pig models. Compounds with a long duration of action and good therapeutic index were identified and AZD8683 was selected for progression to the clinic.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Antagonistas Muscarínicos
/
Cicloheptanos
/
Enfermedad Pulmonar Obstructiva Crónica
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2013
Tipo del documento:
Article