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

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Author(s)

Abstract

A novel lead compound, <i>N</i>-{3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl}-1-methyl-5-oxo-<i>N</i>-phenylpyrrolidine-3-carboxamide (1), was identified as a CCR5 antagonist by high-throughput screening using [<sup>125</sup>I]RANTES and CCR5-expressing CHO cells. The IC<sub>50</sub> value of 1 was 1.9 μ<small>M</small>. 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, IC<sub>50</sub>=0.057 μ<small>M</small>; 11b, IC<sub>50</sub>=0.050 μ<small>M</small>) or replacing the 1-methyl group of the 5-oxopyrrolidine moiety with a 1-benzyl group (12e, IC<sub>50</sub>=0.038 μ<small>M</small>) 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 IC<sub>50</sub> values of 0.44, 0.19, and 0.49 μ<small>M</small>, respectively.

Journal

  • Chemical and Pharmaceutical Bulletin

    Chemical and Pharmaceutical Bulletin 52(1), 63-73, 2004-01-01

    The Pharmaceutical Society of Japan

References:  34

Codes

  • NII Article ID (NAID)
    110003615479
  • NII NACSIS-CAT ID (NCID)
    AA00602100
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    00092363
  • NDL Article ID
    6794839
  • NDL Source Classification
    ZS51(科学技術--薬学) // ZP1(科学技術--化学・化学工業)
  • NDL Call No.
    Z53-D167
  • Data Source
    CJP  NDL  NII-ELS  J-STAGE 
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