title: Characterization of YM-90709 as a novel antagonist which inhibits the binding of interleukin-5 to interleukin-5 receptor.
abstract: Interleukin-5 (IL-5) plays an important role in the activation of eosinophils in allergic inflammation including asthma 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, is reported here to inhibit the binding of IL-5 to its receptor on peripheral human eosinophils and butyric acid-treated eosinophilic HL-60 clone 15 cells, with IC50 values of 1.0 and 0.57 microM, respectively. In contrast, YM-90709 did not affect the binding of granulocyte-macrophage colony-stimulating factor (GM-CSF) to its receptor on eosinophils and eosinophilic HL-60 clone 15 cells. In functional assays, YM-90709 inhibited IL-5-prolonged eosinophil survival with an IC50 value of 0.45 microM and did not affect the GM-CSF-prolonged eosinophil survival. Furthermore, YM-90709 inhibited the IL-5-induced but not GM-CSF-induced tyrosine phosphorylation of Janus kinase 2 (JAK2) in eosinophilic HL-60 clone 15 cells. These results indicate that YM-90709 is a novel IL-5 inhibitor which selectively blocks the binding of IL-5 to the IL-5 receptor (IL-5R).
authors.affiliation: Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.. 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. morokata@yamanouchi.co.jp
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
authors.forename: Kenji
authors.initials: K
authors.lastname: Ida
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Yamada
mesh_terms: D018926:Anti-Allergic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D015848:Interleukin-5 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D053614:Janus Kinase 2; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011810:Quinoxalines / Q000494:pharmacology*; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053649:Receptors, Interleukin-5
chemical_list: C475470:2,3-dimethoxy-6,6-dimethyl-5,6-dihydrobenzo(7,8)indolizino (2,3-b)quinoxaline; D018926:Anti-Allergic Agents; D007211:Indoles; D015848:Interleukin-5; D011518:Proto-Oncogene Proteins; D011810:Quinoxalines; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D019000:Phosphotyrosine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2