RESUMEN
A series of novel biphenyl piperazines was discovered as highly potent muscarinic acetylcholine receptor antagonists via high throughput screening and subsequent optimization. Compound 5c with respective 500- and 20-fold subtype selectivity for M3 over M2 and M1 exhibited excellent inhibitory activity and long duration of action in a bronchoconstriction in vivo model in mice via intranasal administration. The novel inhaled mAChR antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease.
Asunto(s)
Broncoconstricción/efectos de los fármacos , Broncodilatadores/farmacología , Piperazinas/farmacología , Receptores Muscarínicos/efectos de los fármacos , Administración Intranasal , Animales , Pruebas de Provocación Bronquial , Broncoconstrictores/farmacología , Broncodilatadores/síntesis química , Broncodilatadores/química , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Cloruro de Metacolina/farmacología , Ratones , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
High throughput screening and subsequent optimization led to the discovery of novel quaternary ammonium salts as highly potent muscarinic acetylcholine receptor antagonists with excellent selectivity. Compounds 8a, 13a, and 13b showed excellent inhibitory activity and long duration of action in bronchoconstriction in vivo models in two species via intranasal or intratracheal administration. The novel inhaled muscarinic receptor antagonists are potentially useful therapeutic agents for the treatment of chronic obstructive pulmonary disease and other bronchoconstriction disorders.
Asunto(s)
Antagonistas Muscarínicos/farmacología , Compuestos de Fenilurea/farmacología , Compuestos de Amonio Cuaternario/farmacología , Tirosina/análogos & derivados , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Broncoconstricción/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Cobayas , Ratones , Ratas , Tirosina/farmacologíaRESUMEN
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.