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ID: ALA1139410

Journal: Bioorg Med Chem

Title: Potent CCR4 antagonists: synthesis, evaluation, and docking study of 2,4-diaminoquinazolines.

Authors: Yokoyama K, Ishikawa N, Igarashi S, Kawano N, Masuda N, Hattori K, Miyazaki T, Ogino S, Orita M, Matsumoto Y, Takeuchi M, Ohta M.

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).

CiteXplore: 18694645

DOI: 10.1016/j.bmc.2008.07.062