Novel CC chemokine receptor 4 antagonist RS-1154 inhibits ovalbumin-induced ear swelling in mice.
CC chemokine ligand 17 (CCL17/thymus and activation-regulated chemokine: TARC) and CCL22 (macrophage-derived chemokine: MDC) selectively bind to CC chemokine receptor 4 (CCR4). The CCR4 system is considered to be responsible for the pathology of allergic diseases such as atopic dermatitis. To find and develop potential medicines against allergic diseases, we screened an in-house library to search for compounds having a profile as a CCR4 antagonist. From among the screening hits, we focused on 3-{2-[(2R)-2-phenyl-4-(4-pyridin-4-ylbenzyl)morpholin-2-yl]ethyl}quinazoline-2,4(1H,3H)-dione (named RS-1154), which had been newly synthesized in our laboratory. This compound inhibited the binding of [(125)I]CCL17 to human CCR4-expressing CHO cells with an IC(50) value of 27.7 nM and moreover inhibited CCL17-induced migration of DO11.10 mice-derived T helper 2 cells with an IC(50) value of 1.5 nM in vitro. We then examined the effect of RS-1154 in an ovalbumin-induced ear swelling assay. The ear thickness was decreased by intravenous administration of anti-CCL17 or anti-CCL22 antibodies, suggesting that the CCR4 system is involved in the ear swelling. Though partially, the oral administration of RS-1154 also significantly ameliorated the ear swelling at the doses of 30 and 100 mg/kg. Furthermore, the serum level of interleukin-4 decreased after the administration of RS-1154. In this study, we succeeded in obtaining a newly-synthesized compound, RS-1154, which has a potential to inhibit the chemotaxis of T helper 2 cells in vitro and to ameliorate ovalbumin-induced ear swelling in vivo. These results raise the possibility that RS-1154 or one of derivatives might become a therapeutic agent for atopic dermatitis patients.
Nakagami
Yasuhiro
Y
Biological Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. nakagami.yasuhiro.y4@daiichisankyo.co.jp
Kawashima
Kayo
K
Yonekubo
Kazuki
K
Etori
Maki
M
Jojima
Takaaki
T
Miyazaki
Shojiro
S
Sawamura
Ryoko
R
Hirahara
Kazuki
K
Nara
Futoshi
F
Yamashita
Makoto
M
D000284:Administration, Oral; D000818:Animals; D001681:Biological Assay; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D004427:Ear Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D020128:Inhibitory Concentration 50; D015847:Interleukin-4 / Q000097:blood / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D010047:Ovalbumin / Q000276:immunology*; D052999:Quinazolinones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000378:metabolism
C547830:3-(2-(2-phenyl-4-(4-pyridin-4-ylbenzyl)morpholin-2-yl)ethyl)quinazoline-2,4(1H,3H)-dione; D003879:Dermatologic Agents; D009025:Morpholines; D052999:Quinazolinones; D054398:Receptors, CCR4; D015847:Interleukin-4; D010047:Ovalbumin