Design, synthesis, and pharmacological evaluation of glutamate carboxypeptidase II (GCPII) inhibitors based on thioalkylbenzoic acid scaffolds.
J Med Chem
; 55(12): 5922-32, 2012 Jun 28.
Article
en En
| MEDLINE
| ID: mdl-22642259
ABSTRACT
A series of thiol-based glutamate carboxypeptidase II (GCPII) inhibitors have been synthesized with either a 3-(mercaptomethyl)benzoic acid or 2-(2-mercaptoethyl)benzoic acid scaffold. Potent inhibitors were identified from each of the two scaffolds with IC(50) values in the single-digit nanomolar range, including 2-(3-carboxybenzyloxy)-5-(mercaptomethyl)benzoic acid 27c and 3-(2-mercaptoethyl)biphenyl-2,3'-dicarboxylic acid 35c. Compound 35c was found to be metabolically stable and selective over a number of targets related to glutamate-mediated neurotransmission. Furthermore, compound 35c was found to be orally available in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Benzoatos
/
Diseño de Fármacos
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Glutamato Carboxipeptidasa II
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Inhibidores Enzimáticos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos