Discovery of TD-4306, a long-acting ß2-agonist for the treatment of asthma and COPD.
Bioorg Med Chem Lett
; 24(13): 2871-6, 2014 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-24835980
ABSTRACT
A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled ß2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing ß2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic ß2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective ß2-agonist with potential for once-daily dosing.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Asma
/
Receptores Adrenérgicos beta 2
/
Quinolonas
/
Doença Pulmonar Obstrutiva Crônica
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Difenilamina
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Descoberta de Drogas
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Agonistas de Receptores Adrenérgicos beta 2
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article