| Project/Area Number |
16K08378
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Chiba Institute of Science |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | カルボキシルエステラーゼ / プロドラッグ / 臓器特異的 / アトルバスタチンプロドラッグ / インドメタシンプロドラッグ / ハロペリドールプロドラッグ / CES1A1 / CES2A1 / 代謝酵素 / 臓器特異的発現機構 / ヒト肝ミクロソーム / ヒト小腸ミクロソーム / アトルバスタチン / PON |
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| Outline of Final Research Achievements |
In this study, we also attempted to study the structure-activity relationship between the structure of the prodrug and the converting enzyme by creating a prodrug metabolism model organ cell for each converting enzyme and actually synthesizing the prodrug. As a result of examining metabolic activation of atorvastatin prodrugs, indomethacin prodrugs, and haloperidol prodrugs, which are prodrugs that express prodrug conversion enzymes and newly formulated prodrugs, hydrolytic activity changes depending on differences in structure or electron density To obtain new findings related to structure-activity relationships. As a result of this result, useful knowledge on prodrug design was obtained as knowledge of structure-activity relationship accompanying optimization of lead compounds in clinical drug development.
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| Academic Significance and Societal Importance of the Research Achievements |
今回の研究の結果、構造、あるいは電子密度の違いにより、加水分解活性能が変化することを明らかにし、さらに置換基の違いによる加水分解活性の変化を明らかにし, 構造活性相関に関わる新規の知見を得た。したがって、臨床医薬品開発におけるリード化合物の最適化に伴う構造活性相関の知見として、各臓器で効率的に代謝活性化されるプロドラッグ設計に関する有用な知見が得られ、新規創薬に有用な知見を与えるものと考えられた。
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