Novel orally bioavailable gamma-secretase inhibitors with excellent in vivo activity.
J Med Chem
; 52(11): 3441-4, 2009 Jun 11.
Article
em En
| MEDLINE
| ID: mdl-19432431
ABSTRACT
The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED(50) of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
/
Tiadiazóis
/
Peptídeos beta-Amiloides
/
Ciclo-Octanos
/
Secretases da Proteína Precursora do Amiloide
Limite:
Animals
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article