Stereoselective synthesis of constrained azacyclic hydroxyethylene isosteres as aspartic protease inhibitors: dipolar cycloaddition and related methodologies toward branched pyrrolidine and pyrrolidinone carboxylic acids.
J Org Chem
; 70(17): 6746-56, 2005 Aug 19.
Article
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| MEDLINE
| ID: mdl-16095294
ABSTRACT
The synthesis of three vicinally substituted azacyclic carboxylic acids in enantiopure form was achieved from a common alpha-amino aldehyde originating from l-leucine. Pyrrolidines and pyrrolidinones were elaborated from alpha,beta-unsaturated gamma-hydroxy-delta-amino acids via azomethine ylide 1,3-dipolar addition and conjugate addition/cyclization strategies, respectively. The azacyclic amino acids were incorporated in a pseudopeptide now encompassing a hydroxyethylene isostere. Low nanomolar inhibition of BACE1, an enzyme implicated in the cascade of events leading to plaque formation in Alzheimer's disease, was found with a pyrrolidinone analogue.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Inhibidores de Proteasas
/
Pirrolidinas
/
Pirrolidinonas
/
Ácidos Carboxílicos
/
Ácido Aspártico Endopeptidasas
Idioma:
En
Revista:
J Org Chem
Año:
2005
Tipo del documento:
Article