Development of 2-Thioxoquinazoline-4-one Derivatives as Dual and Selective Inhibitors of Dynamin-Related Protein 1 (Drp1) and Puromycin-Sensitive Aminopeptidase (PSA)
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- Numadate Akiyoshi
- Institute of Molecular and Cellular Biosciences, The University of Tokyo
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- Mita Yusuke
- Institute of Molecular and Cellular Biosciences, The University of Tokyo
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- Matsumoto Yotaro
- Faculty of Pharma Sciences, Teikyo University
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- Fujii Shinya
- Institute of Molecular and Cellular Biosciences, The University of Tokyo
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- Hashimoto Yuichi
- Institute of Molecular and Cellular Biosciences, The University of Tokyo
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Abstract
An established inhibitor of dynamin-related protein 1 (Drp1), 3-(2,4-dichloro-5-methoxyphenyl)-2-thioxoquinazoline-4-one (mdivi-1), was recently reported also to show potent puromycin-sensitive aminopeptidase (PSA)-inhibitory activity. Herein, we report structural development of mdivi-1 derivatives and structure–activity relationship (SAR) analysis of the synthesized compounds, as well as the structurally related PSA-specific inhibitor 3-(2,6-diethylphenyl)quinazoline-2,4-dione (PAQ-22), with the aim of identifying key structural features for inhibitory activity in order to develop selective inhibitors of Drp1, which is a potential target for treatment of Huntington’s disease. Among the synthesized compounds, 3-(4-chloro-3-methoxyphenyl)-2-thioxoquinazoline-4-one (10g) exhibited more potent Drp1-inhibitory activity than mdivi-1 with high selectivity for Drp1 over PSA.
Journal
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- Chemical and Pharmaceutical Bulletin
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Chemical and Pharmaceutical Bulletin 62 (10), 979-988, 2014
The Pharmaceutical Society of Japan
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Keywords
Details 詳細情報について
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- CRID
- 1390282679155106560
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- NII Article ID
- 130004693775
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- NII Book ID
- AA00602100
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- COI
- 1:STN:280:DC%2BC2M7ms1Shsg%3D%3D
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- ISSN
- 13475223
- 00092363
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- NDL BIB ID
- 025838585
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- PubMed
- 25273056
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- Text Lang
- en
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- Data Source
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- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
- KAKEN
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- Abstract License Flag
- Disallowed