2022 Fiscal Year Final Research Report
Lead discovery for Alzheimer's disease through synthetic organic chemistry
| Project/Area Number |
20K06951
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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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| Review Section |
Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
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| Research Institution | Health Sciences University of Hokkaido |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 天然物合成 / 構造活性相関 / アルツハイマー病 / アミロイドβ凝集阻害剤 / BACE1阻害剤 |
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| Outline of Final Research Achievements |
1. Toward lead discovery of inhibitors of Aβ aggregation, total synthesis of the γ-lactam-containing natural products including talaramide A, rubrobramide, berkeleyamide D, and euvesperins A and B were achieved. Among the synthetic natural products, only berkeleyamide D with a spirocyclic skeleton showed moderate inhibitory activity against Aβ aggregation. In addition, structure-activity relationship (SAR) studies of L-755,807 analogs revealed that a combination of a hydrophobic carbon chain and a terminal hydrophilic functional group is important for Aβ aggregation inhibitory activity.
2. SAR studies of BACE1 inhibitors with a urea functional group led to a discovery of a highly active N,N-dibutylamide derivative.
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| Free Research Field |
有機合成化学、創薬化学
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| Academic Significance and Societal Importance of the Research Achievements |
1. talaramide A、rubrobramide、及び、euvesperin AとBの合成については初のエナンチオ選択的な合成例であり、学術的なインパクトは非常に大きい。また、スピロ構造のberkeleyamide DがAβ凝集阻害活性を示したことや、L-755,807の構造活性相関研究からファーマコフォアを解明できたことは、天然物をリードとしたAβ凝集阻害剤の開発における重要な知見である。
2. 尿素骨格を含む高活性なBACE1阻害剤の創製に成功し、マウスを用いた活性評価においてもある程度の効果を確認できたため、アルツハイマー病治療薬の開発に繋がる成果と期待される。
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