Molecular design of organ-specific prodrugs considering substrate specificity of carboxylesterases
| Project/Area Number |
17K15519
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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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) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | プロドラッグ / 加水分解酵素 / 生体機能利用 / 薬学 / 有機化学 / カルボキシルエステラーゼ / アトルバスタチン / インドメタシン |
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| Outline of Final Research Achievements |
In this project, after clarifying the substrate specificity of human carboxylesterase, which plays an important role in the metabolic activation of ester- and amide-type prodrugs, we design and synthesize prodrugs that are metabolically activated in specific organs. By controlling the steric hindrance and the electron density of the alkoxy group near the ester, we synthesized an indomethacin prodrug that is selectively metabolically activated in human liver microsomes. In addition, by controlling the steric hindrance of the acyl group, a long acting haloperidol prodrug was synthesized.
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| Academic Significance and Societal Importance of the Research Achievements |
医薬品シーズの中には、十分な薬理活性があるものの、体内動態 (吸収・分布・代謝・排泄) において良好な結果が得られず、開発を断念したものが数多く存在する。本研究では、薬物の代謝において主要な役割を果たしている加水分解酵素の性質を解明し、医薬品の構造と代謝速度の関係を明らかにした。さらに、本研究で得られた加水分解酵素の性質を応用し、特定の臓器で特異的に代謝活性化するプロドラッグや作用持続型のプロドラッグの設計及び合成に成功した。
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Report
(3 results)
Research Products
(8 results)
