Potent CCR4 antagonists: synthesis, evaluation, and docking study of 2,4-diaminoquinazolines.
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).
Yokoyama
Kazuhiro
K
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. kazuhiro.yokoyama@jp.astellas.com
Ishikawa
Noriko
N
Igarashi
Susumu
S
Kawano
Noriyuki
N
Masuda
Naoyuki
N
Hattori
Kazuyuki
K
Miyazaki
Takahiro
T
Ogino
Shin-ichi
S
Orita
Masaya
M
Matsumoto
Yuzo
Y
Takeuchi
Makoto
M
Ohta
Mitsuaki
M
D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010081:Oxazolone; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012871:Skin Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C515354:CCR4 protein, human; C515355:Ccr4 protein, mouse; D011799:Quinazolines; D054398:Receptors, CCR4; D010081:Oxazolone; C013474:2,4-diaminoquinazoline