Suzuki Keiko, Morokata Tatsuaki, Morihira Koichiro, Sato Ippei, Takizawa Satoko, Kaneko Masayuki, Takahashi Koichiro, Shimizu Yasuaki
Inflammation Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Japan.
Biochem Biophys Res Commun. 2006 Jan 27;339(4):1217-23. doi: 10.1016/j.bbrc.2005.11.141. Epub 2005 Dec 5.
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.
嗜酸性粒细胞在包括特应性皮炎和哮喘在内的多种疾病中发挥着重要的促炎作用。嗜酸性粒细胞趋化因子-1及其受体CCR3参与嗜酸性粒细胞从血液募集到炎症组织的过程，因此抑制嗜酸性粒细胞趋化因子-1/CCR3的相互作用可能对伴有嗜酸性粒细胞浸润的过敏性炎症具有治疗潜力。YM-344031是一种新型选择性小分子CCR3拮抗剂，能有效抑制配体结合（IC(50)=3.0nM）、配体诱导的Ca(2+)内流（IC(50)=5.4nM）以及人CCR3表达细胞的趋化作用（IC(50)=19.9nM）。对食蟹猴口服给予YM-344031（1-10mg/kg）可显著抑制嗜酸性粒细胞趋化因子-1诱导的全血中嗜酸性粒细胞形态变化。此外，在小鼠过敏模型中，口服给予YM-344031（100mg/kg）可预防速发和迟发性过敏性皮肤反应。因此，YM-344031有潜力成为一种新型的口服化合物，用于治疗过敏性炎症，如特应性皮炎和哮喘。
