Discovery of potent CCR4 antagonists: Synthesis and structure-activity relationship study of 2,4-diaminoquinazolines.
A new series of quinazolines that function as CCR4 antagonists were discovered during the screening of our corporate compound libraries. Subsequent compound optimization elucidated the structure-activity relationships and led the identification of 2-(1,4'-bipiperidine-1'-yl)-N-cycloheptyl-6,7-dimethoxyquinazolin-4-amine 14a, which showed potent inhibition in the [(35)S]GTPgammaS-binding assay (IC(50)=18nM). This compound also inhibited the chemotaxis of human and mouse CCR4-expressing cells (IC(50)=140nM, 39nM).
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. kazuhiro.yokoyama@jp.astellas.com
Kazuhiro
K
Yokoyama
Noriko
N
Ishikawa
Susumu
S
Igarashi
Noriyuki
N
Kawano
Kazuyuki
K
Hattori
Takahiro
T
Miyazaki
Shin-ichi
S
Ogino
Yuzo
Y
Matsumoto
Makoto
M
Takeuchi
Mitsuaki
M
Ohta
D000818:Animals; D002633:Chemotaxis / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D051379:Mice; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C515354:CCR4 protein, human; C515355:Ccr4 protein, mouse; D011799:Quinazolines; D054398:Receptors, CCR4; C013474:2,4-diaminoquinazoline; D016244:Guanosine 5'-O-(3-Thiotriphosphate)