Strategic drug design to avoid metabolic activation of hapatotoxic drugs
| Project/Area Number |
16K08379
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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 | Keio University |
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Principal Investigator |
Ohe Tomoyuki 慶應義塾大学, 薬学部(芝共立), 准教授 (30624283)
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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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 薬物代謝 / 代謝活性化 / 反応性代謝物 / トラッピング剤 / ベンズブロマロン / ジクロフェナク / ネビラピン / リモナバン / 反応性代謝 / ラベタロール / 創薬化学 / 肝毒性 |
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| Outline of Final Research Achievements |
Metabolic activation of drugs to chemically reactive metabolites that are capable of modifying cellular macromolecules results in acute and/or idiosyncratic toxicities. Some marketed drugs are known to generate reactive metabolites and exhibit hepatotoxicity as side effects. These drugs must be carefully used on medication or withdrawn from the market in the worst-case. The current research is aiming to develop improved medicines to reduce the formation of reactive metabolites on the basis of the activation mechanism of three hapatotoxic drugs (benzbromarone, diclofenac, nevirapine).
First of all, we succeeded in the development of a novel fluorescent trapping agent to quantitatively and effectively detect reactive metabolites. Next, we designed and chemically synthesized multiple derivatives of the three drugs to avoid their metabolic activation. It was found that some of the derivatives are not subject to metabolic activation with remaining pharmacological activities as expected.
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| Academic Significance and Societal Importance of the Research Achievements |
まず、本研究で開発した新規蛍光標識トラッピング剤は、今後製薬企業の創薬研究で毒性リスクの低い候補品を創製するための評価系として使用される可能性が高く、将来的に安全性の高い医薬品の創製に貢献できるものと考えられる。また、今回扱った医薬品のうち、特にベンズブロマロンについては有力な候補品の創製に成功しており、この化合物がリード化合物となり新規高尿酸血症治療薬の創製に繋がるかも知れない。また。本研究で取り入れた方法論、すなわち、既存薬の毒性を有機化学的な観点から捉えそれを基に低毒性医薬品を創製する試みは、新薬の創製が難しい現在、既存薬の骨格を有効利用する創薬戦略の一つになることが期待される。
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Report
(4 results)
Research Products
(11 results)
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[Journal Article] Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation.2018
Author(s)
Ohe T, Umezawa R, Kitagawara Y, Yasuda D, Takahashi K, Nakamura S, Abe A, Sekine S, Ito K, Okunushi K, Morio H, Furihata T, Anzai N, Mashino T.
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Journal Title
Bioorg Med Chem Lett
Volume: 28
Issue: 23-24
Pages: 3708-3711
DOI
Related Report
Peer Reviewed / Open Access
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