2023 Fiscal Year Final Research Report
Elongation of half-life time of vitamin D receptor ligands: acquisition of metabolic resistance and development of selective inhibitors against inactivation enzyme of vitamin D
| Project/Area Number |
18K06556
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
|
|---|
| Research Institution | Teikyo University |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
高野 真史 帝京大学, 薬学部, 講師 (50386611)
|
|---|
| Project Period (FY) |
2018-04-01 – 2024-03-31
|
| Keywords | ビタミンD / フッ素原子導入 / ビタミンD受容体 / CYP24A1 / オステオカルシン転写活性 / 代謝抵抗性 |
|---|
| Outline of Final Research Achievements |
From the viewpoint of acquiring metabolic resistance to the specific inactivating enzyme CYP24A1 of vitamin D3, fluorine atoms were introduced from the C22-position of the side chain to the terminal C26,27-positions of vitamin D3. We investigated the effects of the position, number, and stereochemistry of the fluorine atom on CYP24A1 metabolic resistance and binding affinity to specific nuclear receptors (VDRs), which are important for expression of activity. During the period of this research project, we developed synthetic methods to efficiently introduce fluorine from the C23-position of the side chain of the CD ring to the terminal C26,27-positions, succeeded in synthesizing fluorinated 25-hydroxyvitamin D derivatives, and studied basic biological activity. The results were reported in academic journals.
We also obtained a new inhibitor of CYP105A1, which shows the similar metabolic ability to CYP24A1.
|
| Free Research Field |
薬化学
|
| Academic Significance and Societal Importance of the Research Achievements |
活性型ビタミンD3には骨粗鬆症、乾癬、二次性副甲状腺機能亢進症などの治療薬として臨床適用されている。側鎖末端をフッ素化した医薬品には日本で開発されたファレカルシトリオールが知られているが、側鎖の中央部分をフッ素化したビタミンD誘導体の生理活性について、系統的な薬理効果は知られていない。当研究課題ではまずこの課題を克服すべく側鎖を系統的にフッ素化し、様々なA環部とカップリングできるCD環原料を開発した。これを用いて系統的に側鎖フッ素化25-水酸化ビタミンD誘導体を合成し、フッ素を導入した位置、数、立体化学による生物活性への影響をまとめ、医薬品設計への重要な知見を明らかにした。
|
