| Project/Area Number |
15590021
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Teikyo University |
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Principal Investigator |
KITTAKA Atsushi Teikyo University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00214833)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Nozomi Teikyo University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (80349258)
HONZAWA Shinobu Teikyo University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (90311547)
ARAI Midori Teikyo University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (40373261)
SUGIYAMA Toru The University of Tokyo, Department of Life Sciences, Research Associate, 大学院・総合文化研究科, 助手 (40242036)
藤島 利江 帝京大学, 薬学部, 講師 (90286980)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | vitamin D receptor (VDR) / active vitamin D_3 / antagonist / agonist / TEI-9647 / Paget's disease / HL-60 cells / structure activity relationship |
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| Research Abstract |
Recently, compounds with vitamin D receptor (VDR) antagonistic activity have received considerable attention because of their possibility to treat for Paget's disease, which is the second most common bone disease after osteoporosis in Anglo-Saxons. It is known that 1α-hydroxyvitamin D_3-26,23-lactone (TEI-9647) shows VDR antagonistic activity (IC_<50> 8.3 nM), while this compound has low affinity for the VDR and instability in blood. We investigated to enhance the affinity for the VDR and stability in blood by modifying C2α and C24 positions of TEI-9647. In this project, we have developed the short step synthesis of the new CD-ring lactone parts of 24,24-dimethylated TEI-9647 using low-valent Cr-mediated allylation and 24,24-ethano TEI-9647 with a spiro-structure using Ru-catalyzed intermolecular enyne metathesis between alkynone and ethylene to give dienone followed by regioselective cyclopropanation. Stereochemistry at the C23 position on the new side chains of 24,24-dimethyl and 24,24-ethano lactone was determined based on their X-ray crystallographic analyses.
It was found that the synthesized 24,24-dimethylated TEI-9647 showed more than 12 fold higher anti-D activity than that of the first reported VDR-antagonist TEI-9647. Moreover, double modification at both C2α and C24 with methyl groups showed 89 times more potent antagonistic activity (IC_<50> 0.093 nM) than that of TEI-9647. As far as we know, this 2α,24,24-trimethyl analog of TEI-9647 is the most potent VDR-antagonist so far. 2α-Methyl-24,24-ethano analog of TEI-9647 showed more than 19 fold higher anti-D activity than that of TEI-9647.
We believe these analogs with potent anti-D activity would contribute to understanding the mechanisms involved in the expression of antagonistic activity on the VDR as well as to finding the seeds of new medicines for treating patients of Paget's disease.
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