Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Regular Articles
CCR5 Antagonists as Anti-HIV-1 Agents. 1.
Synthesis and Biological Evaluation of 5-Oxopyrrolidine-3-carboxamide Derivatives
Shinichi Imamura, Yuji Ishihara, Taeko Hattori, Osamu Kurasawa, Yoshihiro Matsushita, Yoshihiro Sugihara, Naoyuki Kanzaki, Yuji Iizawa, Masanori Baba, Shohei Hashiguchi
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Keywords: CCR5 antagonist, chemokine, human immunodeficiency virus type 1 (HIV-1), 5-oxopyrrolidine-3-carboxamide
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2004 Volume 52 Issue 1 Pages 63-73

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Abstract

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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© 2004 The Pharmaceutical Society of Japan
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