Novel structure development of vitamin D-derived photoreactive isomers: development of bone effect enhancement and half-life extension molecules in vivo

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K07869
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Teikyo University
• Principal Investigator: KITTAKA ATSUSHI 帝京大学, 薬学部, 教授 (00214833)
• Co-Investigator(Kenkyū-buntansha): 高野 真史 帝京大学, 薬学部, 講師 (50386611)
• Research Collaborator: SAKAKI Toshiyuki
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: ビタミンＤ / ビタミンＤ誘導体 / タキステロール / ビタミンＤ受容体 / 代謝 / X線共結晶構造解析 / 骨形成作用

Outline of Final Research Achievements

According to the synthetic studies on tachysterol derivatives which are few of the prior research examples, a derivative with selective bone formation activity equal to or higher than that of the osteoporosis therapeutic drug eldecalcitol and 7,8-cis-19-norvitamin D derivatives were found. We succeeded in X-ray co-crystal structure analysis in complex with human vitamin D receptor (hVDR).
In addition, the structure of the CYP24A1 metabolite of the active vitamin D3 derivative AH-1, which has a 2α-tetrazole ethyl group, with great bone formation activity was clarified by chemical synthesis. This metabolite retains hVDR binding affinity, has a long half-life time in vivo, and therefore, it is considered to be a cause of the strong in vivo bone formation action of AH-1. A low side effect of hypercalcemia on AH-1 was also demonstrated in osteoporosis model rats.

Free Research Field

有機合成化学

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会の我国には1,000万人を超える骨粗鬆症患者がいる。活性型ビタミンDは、骨に存在する破骨細胞と骨芽細胞の両方に働いて、健全な骨形成サイクルを機能させて質の高い骨形成に重要である。しかし医薬品としての使用は、高カルシウム血症が懸念され、カルシウム活性と骨形成作用との分離が必要である。本研究課題では、これまで研究例の少ないタキステロール骨格に着目し、14位をエピ化させて安定な誘導体の合成に成功した。また、代謝安定性の高いAH-1について、その代謝産物の優れた生物活性知見を得た。骨粗鬆症治療薬への新たな切り口となる。