CCR5 Antagonists as Anti-HIV-1 Agents. 1. Synthesis and Biological Evaluation of 5-Oxopyrrolidine-3-carboxamide Derivatives
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- Imamura Shinichi
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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- Ishihara Yuji
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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- Hattori Taeko
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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- Kurasawa Osamu
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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- Matsushita Yoshihiro
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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- Sugihara Yoshihiro
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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- Kanzaki Naoyuki
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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- Iizawa Yuji
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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- Baba Masanori
- Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University
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- Hashiguchi Shohei
- Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.
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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.
Journal
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- Chemical and Pharmaceutical Bulletin
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Chemical and Pharmaceutical Bulletin 52 (1), 63-73, 2004
The Pharmaceutical Society of Japan
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Keywords
Details 詳細情報について
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- CRID
- 1390282679147976064
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- NII Article ID
- 110003615479
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- NII Book ID
- AA00602100
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- ISSN
- 13475223
- 00092363
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- NDL BIB ID
- 6794839
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- PubMed
- 14709870
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
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- Abstract License Flag
- Disallowed