Discovery of (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796): a gamma-secretase inhibitor with Abeta lowering activity in a transgenic mouse model of Alzheimer's disease.
Bioorg Med Chem Lett
; 17(14): 4006-11, 2007 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-17502137
ABSTRACT
We report on the design of benzodiazepinones as peptidomimetics at the carboxy terminus of hydroxyamides. Structure-activity relationships of diazepinones were investigated and orally active gamma-secretase inhibitors were synthesized. Active metabolites contributing to Abeta reduction were identified by analysis of plasma samples from Tg2576 mice. In particular, (S)-2-((S)-2-(3,5-difluorophenyl)-2-hydroxyacetamido)-N-((S,Z)-3-methyl-4-oxo-4,5-dihydro-3H-benzo[d][1,2]diazepin-5-yl)propanamide (BMS-433796) was identified with an acceptable pharmacodynamic and pharmacokinetic profile. Chronic dosing of BMS-433796 in Tg2576 mice suggested a narrow therapeutic window and Notch-mediated toxicity at higher doses.
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Base de dados:
MEDLINE
Assunto principal:
Benzodiazepinonas
/
Alanina
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Inibidores Enzimáticos
/
Secretases da Proteína Precursora do Amiloide
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Doença de Alzheimer
Limite:
Animals
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article