| Project/Area Number |
25460160
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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 |
Drug development chemistry
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
Akaji Kenichi 京都薬科大学, 薬学部, 教授 (60142296)
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| Co-Investigator(Renkei-kenkyūsha) |
HATTORI Yasunao 京都薬科大学, 薬学部, 助教 (20567028)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | プロテアーゼ / 阻害剤 / 疎水性相互作用 / 複合体構造解析 / 縮環構造 / 創薬科学 / 医薬品化学 / プロテアーゼ阻害剤 / SARS / BACE1 |
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| Outline of Final Research Achievements |
Evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) was achieved. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site group to the main-chain nitrogen atom of the P2 position via a methylene linker. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CLpro, which confirmed the fused ring structure functions as a novel scaffold for SARS 3CLpro inhibitor.
Hydroxyethylamine (HEA) isostere, as a transition state mimic, was incorporated into macro-cyclic structures connecting the P2 and P4 site of the substrate sequence of BACE1, a key protease for the onset of Alzheimer diseases. Synthesized cyclic inhibitor showed moderate but clear inhibitory activity for BACE1, which confirmed the ring structure functions as a novel scaffold for BACE1 inhibitor.
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