RESUMO
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.
Assuntos
Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Piperazinas/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Administração Intranasal , Animais , Testes de Provocação Brônquica , Broncoconstritores/farmacologia , Broncodilatadores/síntese química , Broncodilatadores/química , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Cloreto de Metacolina/farmacologia , Camundongos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas Muscarínicos/farmacologia , Compostos de Fenilureia/farmacologia , Compostos de Amônio Quaternário/farmacologia , Tirosina/análogos & derivados , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Broncoconstrição/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Cobaias , Camundongos , Ratos , Tirosina/farmacologiaRESUMO
In the course of our research program to develop novel muscarinic receptor antagonists for the treatment of COPD, new tropane carbamate derivatives were identified as potent anti-muscarinic agents. The synthesis, structure-activity relationships and pharmacological evaluation that led to the identification of compound 5o, are described.