In vitro and in vivo characterization of a novel CCR3 antagonist, YM-344031.
Eosinophils play a prominent proinflammatory role in a broad range of diseases, including atopic dermatitis and asthma. Eotaxin-1 and its receptor CCR3 are implicated in the recruitment of eosinophils from blood into inflammatory tissues, therefore inhibition of Eotaxin-1/CCR3 interaction may have therapeutic potential for allergic inflammation with eosinophil infiltration. YM-344031, a novel and selective small molecule CCR3 antagonist, potently inhibited ligand binding (IC(50)=3.0nM), ligand-induced Ca(2+) flux (IC(50)=5.4nM), and the chemotaxis of human CCR3-expressing cells (IC(50)=19.9nM). YM-344031 (1-10mg/kg) orally administered to cynomolgus monkeys significantly inhibited Eotaxin-1-induced eosinophil shape change in whole blood. Additionally, orally administered YM-344031 (100mg/kg) prevented both immediate- and late-phase allergic skin reactions in a mouse allergy model. YM-344031 therefore has potential as a novel and orally available compound for the treatment of allergic inflammation, such as atopic dermatitis and asthma.
Suzuki
Keiko
K
Inflammation Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan. keiko-suzuki@jp.astellas.com
Morokata
Tatsuaki
T
Morihira
Koichiro
K
Sato
Ippei
I
Takizawa
Satoko
S
Kaneko
Masayuki
M
Takahashi
Koichiro
K
Shimizu
Yasuaki
Y
D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage*; D000818:Animals; D002478:Cells, Cultured; D003872:Dermatitis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011726:Pyridinium Compounds / Q000008:administration & dosage*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000819:agonists* / Q000276:immunology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
D000577:Amides; C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; C508080:N-(1-((6-fluoro-2-naphthyl)methyl)pyrrolidin-3-yl)-2-(1-((3-methyl-1-oxidopyridin-2-yl)carbonyl)piperidin-4-ylidene)acetamide; D011726:Pyridinium Compounds; D054397:Receptors, CCR3; D019707:Receptors, Chemokine