Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design.
J Med Chem
; 56(5): 1843-52, 2013 Mar 14.
Article
em En
| MEDLINE
| ID: mdl-23374014
ABSTRACT
ß-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-ß peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 µM to 27 µM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fenilacetatos
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Inibidores de Proteases
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Ácido Aspártico Endopeptidases
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Benzenoacetamidas
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Secretases da Proteína Precursora do Amiloide
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Reino Unido