Rational design and combinatorial evaluation of enzyme inhibitor scaffolds: identification of novel inhibitors of matrix metalloproteinases.
J Med Chem
; 41(13): 2194-200, 1998 Jun 18.
Article
en En
| MEDLINE
| ID: mdl-9632351
ABSTRACT
The discovery of a novel series of heterocyclic matrix metalloproteinase (MMPs) inhibitors is described. Published crystal structures of peptidyl hydroxamates bound to MMPs were the basis for the rational design of diketopiperazine (DKP) inhibitors. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1, stromelysin-1, and gelatinase-B substrate hydrolysis. Deconvolution of active pools resulted in the identification of potent inhibitors (IC50's < 100 nM) of collagenase-1 and gelatinase-B, with the most potent inhibitor exhibiting an IC50 of 30 nM against collagenase-1. A description of the combinatorial evaluation process, as well as initial SAR interpretation for this novel series, is provided.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Metaloendopeptidasas
/
Diseño de Fármacos
/
Inhibidores Enzimáticos
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1998
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA