Inhalation by design: novel tertiary amine muscarinic M3 receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.
J Med Chem
; 54(19): 6888-904, 2011 Oct 13.
Article
em En
| MEDLINE
| ID: mdl-21870878
ABSTRACT
A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Azetidinas
/
Broncodilatadores
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Doença Pulmonar Obstrutiva Crônica
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Receptor Muscarínico M3
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Ácidos Difenilacéticos
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article