Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach.
Bioorg Med Chem Lett
; 21(24): 7277-80, 2011 Dec 15.
Article
en En
| MEDLINE
| ID: mdl-22061640
ABSTRACT
Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aß42 levels in mice and rats.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fenilacetatos
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Piperidinas
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Antiinflamatorios no Esteroideos
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Inhibidores Enzimáticos
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Secretasas de la Proteína Precursora del Amiloide
Límite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos