RS-1748, a novel CC chemokine receptor 4 antagonist, inhibits ovalbumin-induced airway inflammation in guinea pigs.
CC chemokine receptor 4 (CCR4) is generally recognized as a preferential marker for T helper 2 cells, and we have previously reported morpholine-derivative CCR4 antagonists, RS-1154 and RS-1269. Here, we investigate the pharmacological profiles of a novel pyrimidine-derivative CCR4 antagonist, 2-{4-[2-(diethylamino)ethoxy]phenyl}-N-(2,4-difluorobenzyl)-5-fluoropyrimidin-4-amine (RS-1748), which showed potency to inhibit the bindings of [(125)I]CCL17 and [(35)S]GTPgammaS to human CCR4-expressing Chinese hamster ovary (CHO) cells with IC(50) values of 59.9 nM and 18.4 nM, respectively. Furthermore, RS-1748 inhibited ovalbumin-induced airway inflammation in guinea pigs at a dose of 10 mg/kg. These results indicate that RS-1748 would be a promising lead compound for developing a therapeutic agent against asthma.
Nakagami
Yasuhiro
Y
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. nakagami.yasuhiro.y4@daiichisankyo.co.jp
Kawase
Yumi
Y
Yonekubo
Kazuki
K
Nosaka
Emi
E
Etori
Maki
M
Takahashi
Sakiko
S
Takagi
Nana
N
Fukuda
Takeshi
T
Kuribayashi
Takeshi
T
Nara
Futoshi
F
Yamashita
Makoto
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D016466:CHO Cells; D054414:Chemokine CCL17 / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008297:Male; D010047:Ovalbumin; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*
C554823:2-(4-(2-(diethylamino)ethoxy)phenyl)-N-(2,4-difluorobenzyl)-5-fluoropyrimidin-4-amine; D000893:Anti-Inflammatory Agents; D054414:Chemokine CCL17; D011743:Pyrimidines; D054398:Receptors, CCR4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D010047:Ovalbumin