A dual antagonist for chemokine CCR3 receptor and histamine H1 receptor.
Eosinophilic chemokines and histamine play distinct but important roles in allergic diseases. Inhibition of both eosinophilic chemokines and histamine, therefore, is an ideal strategy for the treatment of allergic inflammation, such as asthma, allergic rhinitis, and atopic dermatitis. YM-344484 was found to potently inhibit both the CCL11-induced Ca2+ influx in human CCR3-expressing cells (Kb=1.8 nM) and histamine-induced Ca2+ influx in histamine H1 receptor-expressing PC3 cells (Kb=47 nM). YM-344484 also inhibited the CCL11-induced chemotaxis of human CCR3-expressing cells (IC50=6.2 nM) and CCL11-induced eosinophil-derived neurotoxin release from human eosinophils (IC50=19 nM). Orally administered YM-344484 inhibited the increase in histamine-induced vascular permeability in mice (82% inhibition at a dose of 10 mg/kg) and the accumulation of eosinophils in a mouse asthma model (74% at a dose of 300 mg/kg). These results indicate that YM-344484, a novel and functional dual antagonist for chemokine CCR3 receptor and histamine H1 receptor, is an attractive candidate for development as a novel anti-allergic inflammation drug.
Suzuki
Keiko
K
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Osaka 532-8514, 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
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced / Q000150:complications; D020013:Calcium Signaling / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D047208:Eosinophil-Derived Neurotoxin / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006632:Histamine / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D010880:Piperidines / Q000494:pharmacology*; D011014:Pneumonia / Q000209:etiology / Q000517:prevention & control; D011657:Pulmonary Eosinophilia / Q000209:etiology / Q000517:prevention & control; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000378:metabolism; D012867:Skin / Q000098:blood supply; D014162:Transfection
D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; C515350:CCR3 protein, human; C515351:Ccr3 protein, mouse; C515352:Ccr3 protein, rat; D006633:Histamine Antagonists; C521599:N-(1-((6-fluoro-2-naphthyl)methyl)pyrrolidin-3-yl)-2-(1-((6-methylpyridazin-3-yl)carbonyl)piperidin-4-ylidene)acetamide; D010880:Piperidines; D011724:Pyridazines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D011969:Receptors, Histamine H1; D006632:Histamine; D010047:Ovalbumin; D047208:Eosinophil-Derived Neurotoxin