Potent and orally bioavailable CCR4 antagonists: Synthesis and structure-activity relationship study of 2-aminoquinazolines.
Starting with a series of CC chemokine receptor-4 (CCR4) antagonists developed in a previous study, the potency was improved by replacing the pyrrolidine moiety of N-(4-chlorophenyl)-6,7-dimethoxy-2-(4-pyrrolidin-1-ylpiperidin-1-yl)quinazolin-4-amine 2 with a 3-(hydroxymethyl)piperidine. The resulting compound (1'-{4-[(4-chlorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}-1,4'-bipiperidin-3-yl)methanol 8ic was a strong inhibitor of human/mouse chemotaxis. Oral administration of 8ic showed anti-inflammatory activity in a murine model of acute dermatitis (oxazolone-induced contact hypersensitivity test) in a dose-dependent manner.
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
Hamaguchi
Wataru
W
Yamasaki
Shingo
S
Koganemaru
Yohei
Y
Hattori
Kazuyuki
K
Miyazaki
Takahiro
T
Ogino
Shin-Ichi
S
Matsumoto
Yuzo
Y
Takeuchi
Makoto
M
Ohta
Mitsuaki
M
D000284:Administration, Oral; D000588:Amines; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D002633:Chemotaxis / Q000187:drug effects; D003872:Dermatitis / Q000188:drug therapy; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D010880:Piperidines; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000588:Amines; D000893:Anti-Inflammatory Agents; D010880:Piperidines; D011799:Quinazolines; D054398:Receptors, CCR4