Discovery of small molecular (D)-leucinamides as potent, Notch-sparing γ-secretase modulators.
Eur J Med Chem
; 79: 143-51, 2014 May 22.
Article
en En
| MEDLINE
| ID: mdl-24732790
ABSTRACT
Structural optimization of the prior lead 3 led to the small molecular (D)-leucinamides with potent modulating activity and Notch-sparing selectivity on the proteolytic processing of amyloid-ß precursor proteins. The N-(R)-epoxypropyl analog 10c exhibited potent γ-secretase modulation compared to DAPT and showed substantial substrate selection for APP cleavage over Notch cleavage, while N-(2-fluoro)benzyl analog 10e showed the most potent γ-secretase inhibition with dull selectivity. The exceptional suppression of ERK-mediated activation suggested that these potent γ-secretase modulators may adapt an alternative pathway to prominently induce the differential inhibition of C99 cleavage by γ-secretase.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Secretasas de la Proteína Precursora del Amiloide
/
Bibliotecas de Moléculas Pequeñas
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Descubrimiento de Drogas
/
Leucina
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2014
Tipo del documento:
Article
País de afiliación:
Taiwán
Pais de publicación:
FR
/
FRANCE
/
FRANCIA
/
FRANÇA