Design and Synthesis of Vitamin D Receptor Antagonists : Remedy for Pagets Desease

维生素 D 受体拮抗剂的设计与合成：治疗佩吉特病

• 批准号: 15590021
• 负责人: KITTAKA Atsushi
• 金额: $ 2.3万
• 依托单位: Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590021/
• 关键词: vitamin D receptor (VDR); active vitamin D_3; antagonist; agonist; TEI-9647; Paget's disease; HL-60 cells; structure activity relationship

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.

最近，具有维生素D接收器（VDR）拮抗活性的化合物因其治疗Paget疾病的可能性而受到了考虑，这是盎格鲁撒克逊骨质骨质疏松症的第二个最常见的骨病。众所周知，1α-羟基维生素D_3-26,23-内酮（TEI-9647）显示VDR拮抗活性（IC_ <50> 8.3 nm），而该化合物对血液中的VDR和不稳定性的亲和力较低。我们研究了通过修改TEI-9647的C2α和C24位置，以增强对血液中VDR和稳定性的亲和力。在这个项目中，我们使用低价值CR介导的倾斜倾斜的新型CD-CD环内酯部分的短步综合了24,24-二甲基化的TEI-9647和24,24-Ethano Tei-9647，并使用ru-cataly-cataly-cataly-cational-cational in ru-cartory in ru-cartotaled-croploperate in cr-croptore in cy ru-cartoperate in cy ru cartopartire。 C23位置在24,24-二甲基和24,24-乙醇内酯的新侧链中处于其X射线晶体学分析的确定。它发现合成的24,24-二甲基化的TEI-9647表现出比第一个报告的vdr-9647的抗D活性更高的抗D活性。此外，用甲基的C2α和C24进行双重修饰，其潜在拮抗活性（IC_ <50> 0.093 nm）比TEI-9647高89倍。据我们所知，迄今为止，TEI-9647的2α，24,24-三甲基类似物是最潜在的VDR-Antagonist。 TEI-9647的2α-甲基-24,24-ethano类似物的抗D活性比TEI-9647的抗D活性高19倍。我们相信这些具有潜在抗D活性的类似物将有助于理解VDR上拮抗活性的机制，并在VDR上表达拮抗作用，并为治疗Pagaget疾病患者的新药物的种子而言。

项目成果

Synthesis of an A-Ring Synthon of 2α-Substituted Vitamin D_3 Analogues Utilizing Grignard Reaction Towards Methyl 2,3-Anhydro-4,6-O-benzylidene-α-D-mannopyranoside

利用甲基2,3-脱水-4,6-O-亚苄基-α-D-吡喃甘露糖苷的格氏反应合成2α-取代维生素D_3类似物的A环合成物

• 发表时间: 2003
• 期刊: Heterocycles 61
• 作者: Shinobu Honzawa;Yasuhiro Yamamoto;Koshiro Hirasaka;Hiroaki Takayama;Atsushi Kittaka
• 通讯作者: Atsushi Kittaka

橘高敦史(翻訳): "メディシナルケミストリー 第5章「受容体での薬物作用」"丸善株式会社(東京・日本橋). 597(27) (2003)

Atsushi Tachibana（译者）：“药物化学第 5 章“受体的药物作用”Maruzen Co., Ltd.（日本桥，东京）。597(27) (2003)

Efficient and Convergent Coupiing Route for the Short-step Synthesis of Enantio-pure 2α- and 2β-Alkylated 1α,25-Dihydroxy-19-norvitamin D_3 Analogues

用于短步合成对映纯 2α- 和 2β-烷基化 1α,25-二羟基-19-去甲维生素 D_3 类似物的高效收敛偶联路线

• 发表时间: 2003
• 期刊: Sunlett 8号
• 作者: Akihiro Yoshida;et al.
• 通讯作者: et al.

Synthesis of 2-Modified 1α,25-Dihydroxy-19-norvitamin D_3 with Julia Olefination: High Potency in Induction of Differentiation on HL-60 Cells

用 Julia 烯化合成 2-修饰 1α,25-二羟基-19-去甲维生素 D_3：高效诱导 HL-60 细胞分化

• 发表时间: 2003
• 期刊: J.Org.Chem. 68(19)
• 作者: Keiichiro Ono;Akihiro Yoshida;Nozomi Saito;Toshie Fujishima;Shinobu Honzawa;Yoshitomo Suhara;Seishi Kishimoto;Takayuki Sugiura;Keizo Waku;Hiroaki Takayama;Atsushi Kittaka
• 通讯作者: Atsushi Kittaka

Keiichiro Ono, et al.: "Synthesis of 2-Modified 1α,25-Dihydroxy-19-norvitamin D_3 with Julia Olefination : High Potency in Induction of Differentiation on HL-60 Cells"The Journal of Organic Chemistry. 68・19. 7407-7415 (2003)

Keiichiro Ono 等人：“用 Julia 烯化合成 2-修饰的 1α,25-二羟基-19-去甲维生素 D_3：诱导 HL-60 细胞的高效能”有机化学杂志 68・19。 -7415 (2003)