| Project/Area Number |
18K14359
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 37030:Chemical biology-related
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| Research Institution | Hiroshima International University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | FXR |
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| Outline of Final Research Achievements |
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection.To date, therefore, the activation of FXR leads to considerable interest in FXR as potential therapeutic targets.
We explored of novel type of FXR agonists/antagonists focusing on benzimidazole scaffold in the structure.For FXR antagonists, we have revealed the pharmacophore and PK profile adjustable regions required to maintain activity with a comprehensive understanding of structure-activity relationships. In addition, N-substituted benzimidazole, which was a key building block of FXR antagonist, was applied as a part of FXR agonist.
We have succeeded in finding a highly potent and active FXR ligands. In addition, the interaction between FXR-LBD and these ligands, which seems to be necessary for each pharmacological activation, is being clarified, and the core of "activate swich" can be approached.
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| Academic Significance and Societal Importance of the Research Achievements |
申請者は、これまでのリガンド探索において、薬理活性発現に関わる重要な相互作用部位を明らかにするとともに、FXR agonist/antagonist活性の維持において共通するベンゾイミダゾールファーマコフォアを見出すことに成功した。ベンゾイミダゾールファーマコフォアを有するfocused libraryの発展的応用は、agonist/antagonistに固執することのない柔軟な視点でのFXRリガンド開発を可能にするものであり、NAFLD/NASH改善メカニズムをはじめとするメタボリックシンドローム関連治療薬の創製に大きく寄与するものである。
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