Inhibitory effect of the new orally active CCR4 antagonist K327 on CCR4+CD4+ T cell migration into the lung of mice with ovalbumin-induced lung allergic inflammation.
CC chemokine receptor 4 (CCR4) is expressed on Th2 cells, found in inflamed tissues of allergic diseases, and is therefore suspected to be involved in the pathogenesis of allergic diseases by controlling Th2 cell migration into inflamed tissues. The aim of the present study was to investigate the inhibitory effect of a selective CCR4 antagonist, K327 [6-cyclopropancarbonyl-4-(2,4-dichlorobenzylamino)-2-(4-[2-(piperidin-1-yl)ethyl] piperazin-1-yl)-7,8-dihydro-5H-pyrido (4,3-d)pyrimidine], on the recruitment of CCR4+CD4+ T cells to the airway of mice with ovalbumin-induced allergic airway inflammation. K327 was administered to mice in which CCR4+CD4+ T cell accumulation was elicited by multiple inhalations of aerosolized ovalbumin. K327 significantly and dose-dependently inhibited the recruitment of CCR4+CD4+ T cells with an ID(50 )value of 44 mg/kg, p.o. twice daily. The antiasthmatic potential of K327 was also demonstrated by the fact that K327 suppressed the elevation of Th2 cytokines and airway eosinophilia. These results indicate that CCR4 antagonists can control in vivo migration of Th2 cells which express CCR4 and, presumably, serve as a new class of therapeutic agent for allergy.
Sato
Takashi
T
Drug Discovery Research Laboratories, Kyowa Hakko Kirin Co., Ltd., Shizuoka 411-8731, Japan.
Komai
Masato
M
Iwase
Miho
M
Kobayashi
Katsuya
K
Tahara
Harunobu
H
Ohshima
Etsuo
E
Arai
Hitoshi
H
Miki
Ichiro
I
D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004802:Eosinophilia / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
C545456:6-cyclopropancarbonyl-4-(2,4-dichlorobenzylamino)-2-(4-(2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydro-5H-pyrido(4,3-d)pyrimidine; D016207:Cytokines; D011725:Pyridines; D011743:Pyrimidines; D054398:Receptors, CCR4; D010047:Ovalbumin