Discovery of PF-184563, a potent and selective V1a antagonist for the treatment of dysmenorrhoea. The influence of compound flexibility on microsomal stability.
Bioorg Med Chem Lett
; 21(19): 5684-7, 2011 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-21885275
ABSTRACT
The V1a receptor has emerged as an attractive target for a range of indications including Raynaud's disease and dysmenorrhoea. As part of an effort to discover a new class of orally active V1a antagonist, we optimised a highly lipophilic, metabolically unstable lead into a range of potent, selective and metabolically stable V1a antagonists. In this communication, we demonstrate the series-dependent effect of limiting the number of rotatable bonds in order to decrease Cytochrome P450-mediated metabolism. This effort culminated in the discovery of PF-184563, a novel, selective V1a antagonist with excellent in vitro and in vivo properties.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Triazóis
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Benzodiazepinas
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Desenho de Fármacos
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Sistema Enzimático do Citocromo P-450
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Dismenorreia
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Descoberta de Drogas
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Antagonistas dos Receptores de Hormônios Antidiuréticos
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Antagonistas de Hormônios
Limite:
Female
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Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article