Substituted pyrrolidin-2-ones: Centrally acting orexin receptor antagonists promoting sleep. Part 2.
Bioorg Med Chem Lett
; 25(9): 1884-91, 2015 May 01.
Article
em En
| MEDLINE
| ID: mdl-25838147
ABSTRACT
Starting from advanced pyrrolidin-2-one lead compounds, this novel series of small-molecule orexin receptor antagonists was further optimized by fine-tuning of the C-3 substitution at the γ-lactam ring. We discuss our design to align in vitro potency with metabolic stability and improved physicochemical/pharmacokinetic properties while avoiding P-glycoprotein-mediated efflux. These investigations led to the identification of the orally active 3-hydroxypyrrolidin-2-one 46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinonas
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Sono
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Receptores de Orexina
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Antagonistas dos Receptores de Orexina
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article