864355-02-2Relevant academic research and scientific papers
Potent CCR4 antagonists: Synthesis, evaluation, and docking study of 2,4-diaminoquinazolines
Yokoyama, Kazuhiro,Ishikawa, Noriko,Igarashi, Susumu,Kawano, Noriyuki,Masuda, Naoyuki,Hattori, Kazuyuki,Miyazaki, Takahiro,Ogino, Shin-ichi,Orita, Masaya,Matsumoto, Yuzo,Takeuchi, Makoto,Ohta, Mitsuaki
, p. 7968 - 7974 (2008/12/23)
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 ([35S]GTPγS-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 [35S]GTPγS assay results. Administration of 8c in a murine model of acute dermatitis showed anti-inflammatory activity (oxazolone-induced contact hypersensitivity test).
