2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead.
J Med Chem
; 50(18): 4261-4, 2007 Sep 06.
Article
en En
| MEDLINE
| ID: mdl-17685503
ABSTRACT
A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.
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Banco de datos:
MEDLINE
Asunto principal:
Quinazolinas
/
Modelos Moleculares
/
Ácido Aspártico Endopeptidasas
/
Secretasas de la Proteína Precursora del Amiloide
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2007
Tipo del documento:
Article
País de afiliación:
Estados Unidos