JP2011213655A - Ccr2bまたはccr5とフロントタンパク質との相互作用の阻害剤 - Google Patents
Ccr2bまたはccr5とフロントタンパク質との相互作用の阻害剤 Download PDFInfo
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Abstract
Description
別の実施形態において、上記式I中のx1およびx2はともに、塩素または臭素である。
その実施形態において、上記化合物が、上で定義された式IIの化合物である。
本発明の阻害剤および抗炎症剤の有効成分は、上記の式Iで表される化合物またはその塩である。この化合物またはその塩は、フロントタンパク質とCCR2Bとの相互作用を強く阻害する特性を有する。
上述したように、CCR2BとCCR5は非常に高い相同性を有し、細胞内C末端領域のアミノ酸配列で比較した場合にも、CCR2BとCCR5は高い相同性を有する受容体である。フロントタンパク質はこれらの相同性の高いCCR2BとCCR5の両者の細胞内C末端領域に結合する(国際公開第WO2003/070946号)。また、CCR2BおよびCCR5は、(慢性)関節リウマチ、多発性硬化症などの炎症性疾患や、神経性疼痛との関連、癌などの病態形成への関与が示されている。一方、フロントタンパク質もまた、うっ血性心不全、前立腺転移癌、間葉系幹細胞ホーミング制御などの様々な疾患に関係することも知られている。
[実施例1]
フロントタンパク質−CCR2相互作用の阻害活性
フロントタンパク質のC末側配列を含む転写因子の結合ドメイン融合タンパク発現ベクターであるGAL4 BDおよびCCR2のC末側配列を含む活性化ドメイン融合タンパク発現ベクターであるGAL4 ADを、リチウム酢酸/ポリエチレングリコール形質転換プロトコル(Ito et al、J.Bacteriol.153:163−168(1983)を参照)によって、酵母株Y190に形質転換した。このY190/FNT−CCR2酵母株を対数増殖期まで培養した後に、0.5%Westase処理を10分間行ない、酵母を一過性にプロトプラスト化した。ヒスチジン欠損培地に酵母を懸濁し、3−アミノトリアゾール(Sigma Chemical Co.)を終濃度5mMとなるように加え、これを96well plateへアプライした。その後、式IIで表わされる化合物を50μMとなるように添加し、24時間培養を行って、吸光度(800nm)を測定し、相互作用阻害活性をY2Hで検証した。DMSOを加えたコントロールに対して式IIで表わされる化合物の添加により50%程度の相互作用抑制が認められた(図1)。
細胞遊走能の抑制
TAXIScan法(Nitta, et al., Journal of Immunological method;320,155−163(2007))を用いて、式IIで表わされる化合物による細胞遊走能の抑制活性を評価した。
動物での有効性評価試験
ヒツジ赤血球1×106個をマウスに腹腔内投与することにより免疫を行い、足蹠(足裏)の皮下にヒツジ赤血球2×108個を再投与した際の足蹠の肥厚を測定することにより、誘導される細胞性免疫応答の強度を測定した。式IIで表される化合物をDMSOに溶解し、生理食塩水で10倍希釈した溶液500μlを足蹠への再投与の30分前に腹腔内投与し(20、10または5mg/kg)、足蹠の厚みをノギスで測定した。
毒性評価試験
Jurkat細胞にベクターpcMGS−NEOを用いてCCR2を導入して得られたJurkat/CCR2細胞に、式IIで表される化合物(100、10、1または0.1μM)を添加し、48時間培養後、WST−1法にて細胞生存率を測定することにより、毒性評価試験を行った。
Claims (7)
- 前記式Iにおいて、Rがメチルまたはエチルである、請求項1に記載の阻害剤。
- 前記式Iにおいて、x1およびx2はともに塩素または臭素である、請求項1または2に記載の阻害剤。
- 請求項1〜3のいずれか1項に定義される式Iの化合物またはその塩を有効成分として含む抗炎症剤。
- 前記化合物が、請求項4に定義された式IIの化合物である、請求項5に記載の抗炎症剤。
- フロントタンパク質、CCR2BまたはCCR5が関連する炎症性疾患の治療用である、請求項5または6に記載の抗炎症剤。
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