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    Bioorg Med Chem. 2008 Sep 1;16(17):7968-74. Epub 2008 Jul 29.

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

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

    Source

    Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. kazuhiro.yokoyama@jp.astellas.com

    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).

    PMID:
    18694645
    [PubMed - indexed for MEDLINE]

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