Effect of a novel interleukin-5 receptor antagonist, YM-90709 (2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino[2,3-b]quinoxaline), on antigen-induced airway inflammation in BN rats.
Interleukin-5 (IL-5) plays an important role in the activation of eosinophils in the allergic inflammation in conditions such as asthma, rhinitis, and atopic dermatitis. A newly synthesized compound, YM-90709 (2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo[7,8]indolizino[2,3-b]quinoxaline), was previously reported to inhibit the binding of IL-5 to its receptor (R) on human eosinophils and eosinophilic HL-60 clone 15 cells. However, it did not inhibit the binding of granulocyte-macrophage colony-stimulating factor (GM-CSF) to its receptor on the same cells. In this study, the intravenous injection of YM-90709 resulted in the inhibition of antigen-induced infiltration of eosinophils and lymphocytes, but not neutrophils or monocytes, into the bronchoalveolar lavage fluid (BALF) of Brown-Norway (BN) rats, with ED50 values of 0.32 mg/kg and 0.12 mg/kg, respectively. Two glucocorticoids, dexamethasone and prednisolone, inhibited neutrophil, eosinophil, and lymphocyte infiltration into the BALF. However, both significantly reduced the number of peripheral blood leukocytes and bone marrow leukocytes. In contrast, YM-90709 did not affect the peripheral blood leukocytes or the bone marrow leukocytes. These results indicate that, in this model, YM-90709, which is a novel IL-5 R antagonist, inhibits antigen-induced eosinophil and lymphocyte recruitment into the airway, without any suppressive effects on peripheral blood leukocytes or bone marrow leukocytes, in contrast to the glucocorticoids.
Morokata
Tatsuaki
T
Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. morokata@yamanouchi.co.jp
Suzuki
Keiko
K
Ida
Kenji
K
Tsuchiyama
Hirotaka
H
Ishikawa
Jun
J
Yamada
Toshimitsu
T
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D007211:Indoles / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D010047:Ovalbumin / Q000008:administration & dosage; D011014:Pneumonia / Q000097:blood / Q000209:etiology / Q000276:immunology; D011239:Prednisolone / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors*; D053649:Receptors, Interleukin-5
C475470:2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo(7,8)indolizino (2,3-b)quinoxaline; D007211:Indoles; D011810:Quinoxalines; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D003907:Dexamethasone; D010047:Ovalbumin; D011239:Prednisolone