Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14.
Bioorg Med Chem Lett
; 15(7): 1807-10, 2005 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-15780611
ABSTRACT
Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.
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Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Inibidores Enzimáticos
/
Inibidores de Metaloproteinases de Matriz
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2005
Tipo de documento:
Article
País de afiliação:
Estados Unidos