Discovery of novel GSK-3ß inhibitors with potent in vitro and in vivo activities and excellent brain permeability using combined ligand- and structure-based virtual screening.
J Med Chem
; 53(24): 8534-45, 2010 Dec 23.
Article
en En
| MEDLINE
| ID: mdl-21082766
ABSTRACT
Dysregulation of glycogen synthase kinase (GSK-3ß) is implicated in the pathophysiology of many diseases, including type-2 diabetes, stroke, Alzheimer's, and others. A multistage virtual screening strategy designed so as to overcome known caveats arising from the considerable flexibility of GSK-3ß yielded, from among compounds in our in-house database and two commercial databases, new GSK-3ß inhibitors with novel scaffold structures. The two most potent and selective validated hits, a 2-anilino-5-phenyl-1,3,4-oxadiazole (24) and a phenylmethylene hydantoin (28), both exhibited nanomolar affinity and selectivity over CDK2 and were potent enough for direct in vivo validation. Both were able to cause significant increases in liver glycogen accumulation in dose-dependent fashion. One also exhibited excellent blood-brain barrier permeability, the other adequate for a lead compound. Analogues of the oxadiazole 24 were synthesized to experimentally corroborate or rule out ligand-bound structures arising from docking studies. SAR results supported one docking study among a number of alternatives.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Oxadiazoles
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Barrera Hematoencefálica
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Modelos Moleculares
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Relación Estructura-Actividad Cuantitativa
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Glucógeno Sintasa Quinasa 3
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Hidantoínas
/
Compuestos de Anilina
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos