Potent CCR4 antagonists: synthesis, evaluation, and docking study of 2,4-diaminoquinazolines.
Bioorg Med Chem
; 16(17): 7968-74, 2008 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-18694645
ABSTRACT
A series of CC chemokine receptor-4 (CCR4) antagonists were examined in a previous report in an attempt to improve metabolic stability in human liver microsomes. In this study, the cycloheptylamine moiety of N-cycloheptyl-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 1 was replaced with the p-chloroaniline moiety, and the resulting compound, N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine (8c), retained its potency ([(35)S]GTPgammaS-binding inhibition and CCL22-induced chemotaxis in humans/mice). Based on the structure-activity relationships (SAR), a homology model was constructed for CCR4 to explain the binding mode of 8c. Overall, there was good agreement between the docking pose of the CCR4 homology model and the human [(35)S]GTPgammaS assay results. Administration of 8c in a murine model of acute dermatitis showed anti-inflammatory activity (oxazolone-induced contact hypersensitivity test).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
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Simulação por Computador
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Receptores CCR4
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Modelos Químicos
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article