Investigation of α-phenylnorstatine and α-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors.
Bioorg Med Chem
; 19(1): 145-55, 2011 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-21183353
Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and ß-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50)=0.19µM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenilbutiratos
/
Inhibidores de Proteasas
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Ácido Aspártico Endopeptidasas
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Secretasas de la Proteína Precursora del Amiloide
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2011
Tipo del documento:
Article
País de afiliación:
Suecia
Pais de publicación:
Reino Unido