Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics.
Bioorg Med Chem Lett
; 12(24): 3537-41, 2002 Dec 16.
Article
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| MEDLINE
| ID: mdl-12443771
ABSTRACT
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
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Colección:
01-internacional
Asunto principal:
Pirimidinas
/
Inhibidores de la Angiogénesis
/
Receptor 2 de Factores de Crecimiento Endotelial Vascular
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2002
Tipo del documento:
Article
País de afiliación:
Estados Unidos