RESUMO
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.
Assuntos
Amidas/química , Antagonistas Muscarínicos/química , Compostos de Amônio Quaternário/química , Quinuclidinas/química , Receptor Muscarínico M3/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Sítios de Ligação , Broncoconstritores/síntese química , Broncoconstritores/química , Broncoconstritores/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacocinética , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Receptor Muscarínico M3/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Carbamatos/síntese química , Carbamatos/farmacologia , Descoberta de Drogas , Microssomos Hepáticos/efeitos dos fármacos , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/farmacologia , Carbamatos/química , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Antagonistas Muscarínicos/química , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Quinuclidinas/síntese química , Quinuclidinas/química , Quinuclidinas/farmacologia , Fatores de TempoRESUMO
The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.
