New aminoimidazoles as ß-secretase (BACE-1) inhibitors showing amyloid-ß (Aß) lowering in brain.
J Med Chem
; 55(21): 9297-311, 2012 Nov 08.
Article
en En
| MEDLINE
| ID: mdl-23017051
Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aß40 and Aß42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aß was 40-50%, 1.5 h after oral dosing (100 µmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Encéfalo
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Péptidos beta-Amiloides
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Ácido Aspártico Endopeptidasas
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Secretasas de la Proteína Precursora del Amiloide
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Imidazoles
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Suecia
Pais de publicación:
Estados Unidos