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    • CCR5 Antagonists as Anti-HIV-1 Agents. 1. Synthesis and Biological Evaluation of 5-Oxopyrrolidine-3-carboxamide Derivatives

    DOI Web Site Web Site PubMed 被引用文献1件 参考文献43件 オープンアクセス
    • Imamura Shinichi
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
    • Ishihara Yuji
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
    • Hattori Taeko
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
    • Kurasawa Osamu
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
    • Matsushita Yoshihiro
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
    • Sugihara Yoshihiro
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
    • Kanzaki Naoyuki
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
    • Iizawa Yuji
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
    • Baba Masanori
      Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University
    • Hashiguchi Shohei
      Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.

    書誌事項

    公開日
    2004
    資源種別
    journal article
    DOI
    • 10.1248/cpb.52.63
    公開者
    公益社団法人 日本薬学会

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    説明

    A novel lead compound, N-{3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl}-1-methyl-5-oxo-N-phenylpyrrolidine-3-carboxamide (1), was identified as a CCR5 antagonist by high-throughput screening using [125I]RANTES and CCR5-expressing CHO cells. The IC50 value of 1 was 1.9 μM. In an effort to improve the binding affinity of 1, a series of 5-oxopyrrolidine-3-carboxamides was synthesized. Introduction of 3,4-dichloro substituents to the central phenyl ring (10i, IC50=0.057 μM; 11b, IC50=0.050 μM) or replacing the 1-methyl group of the 5-oxopyrrolidine moiety with a 1-benzyl group (12e, IC50=0.038 μM) was found to be effective for improving CCR5 affinity. Compound 10i, 11b, and 12e also inhibited CCR5-using HIV-1 envelope-mediated membrane fusion with IC50 values of 0.44, 0.19, and 0.49 μM, respectively.

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