ethyl 7-((R)-2-((R,E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-1-yl)-5-oxopyrrolidin-1-yl)heptanoate | 1350836-65-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: ethyl 7-((R)-2-((R,E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-1-yl)-5-oxopyrrolidin-1-yl)heptanoate
• 英文别名: ethyl 7-[(2R)-2-[(E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl]heptanoate
• CAS: 1350836-65-5
• 化学式: C₂₃H₃₁F₂NO₄
• 分子量: 423.5
• InChiKey: SGRNLJLJXBPJCJ-VIDFKJSCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  30
• 可旋转键数：
  13
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 7-((R)-2-((R,E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-1-yl)-5-oxopyrrolidin-1-yl)heptanoate 在 四丁基氟化铵 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 mineral oil 为溶剂， 反应 22.08h， 生成 (4-(((4-(2-(((R,E)-4-((R)-1-(7-ethoxy-7-oxoheptyl)-5-oxopyrrolidin-2-yl)-1,1-difluoro-1-phenylbut-3-en-2-yl)oxy)-2-oxoethyl)phenoxy)carbonyl)amino)-1-hydroxybutane-1,1-diyl)diphosphonic acid
  参考文献：
  名称：

  Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis

  摘要：

  There is an important medical need for effective therapies to redress the general bone loss associated with advanced osteoporosis. Prostaglandin E-2 and related EP4 receptor agonists have been shown to stimulate bone regrowth but their use has been limited by systemic side effects. Herein is described the design and synthesis of novel dual-action bone-targeting conjugate pro-drugs where two classes of active agents, a bone growth stimulating prostaglandin E-2 EP4 receptor subtype agonist (5 or 6) and a bone resorption inhibitor bisphosphonate, alendronic acid (1), are coupled using metabolically labile carbamate or 4-hydroxyphenylacetic acid based linkers. Radiolabelled conjugates 9, 11a/b and 25 were synthesized and evaluated in vivo in rats for uptake of the conjugate into bone and subsequent release of the EP4 agonists over time. While conjugate 11a/b was taken up (9.0% of initial dose) but not released over two weeks, conjugates 9 and 25 were absorbed at 9.4% and 5.9% uptake of the initial dose and slowly released with half-lives of approximately 2 weeks and 5 days respectively. These conjugates were well tolerated and offer potential for sustained release and dual synergistic activity through their selective bone targeting and local release of the complimentary active components. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.01.024
• 作为产物：
  描述：

  ethyl 2-(4-iodophenyl)-2-oxoacetate 在 sodium tetrahydroborate 、 正丁基锂 、 甲酸 、 硼氘化钠 、 二乙胺基三氟化硫 、 [((1S,2S)-2-amino-1,2-diphenylethyl)(tosyl)amido](p-cymene)(pyridine)ruthenium(II) tetrafluoroborate 、 palladium diacetate 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 mineral oil 为溶剂， 反应 35.0h， 生成 ethyl 7-((R)-2-((R,E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-en-1-yl)-5-oxopyrrolidin-1-yl)heptanoate
  参考文献：
  名称：

  设计，合成和药代动力学的骨靶向双作用前药治疗骨质疏松症。

  摘要：

  已经设计，合成了双作用的靶向骨的前药，并通过使用差异化双标记方法，在结合到骨骼后评估了其体内和体外的代谢稳定性，体内组织分布以及活性成分的释放速率。衍生品。共轭物（一般结构7）体现了前列腺素EP4受体，化合物5和阿仑膦酸（一种有效的骨吸收抑制剂）非常有效且久经考验的合成代谢选择性激动剂的结合，后者是通过不同的可水解接头单元N-最佳连接的。 4-羧甲基苯基-甲氧基羰基-亮氨酰基-精氨酰基-对氨基苯基甲基醇（Leu-Arg-PABA）。优化的共轭物16旨在使酯酶活性释放5，Leu-Arg-PABA元素的组织蛋白酶K裂解将释放阿仑膦酸。双重放射性标记16的研究为组织蛋白酶K可裂解的肽连接的缀合物用于将双膦酸盐前药靶向骨骼并在体内缓慢释放活性成分提供了概念证明。此类缀合物是用于治疗诸如骨质疏松症的骨疾病的潜在疗法。

  DOI：

  10.1021/acs.jmedchem.6b00951

文献信息

• [EN] AMIDE-LINKED EP4 AGONIST-BISPHOSPHONATE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS AGONISTE D'EP4-BISPHOSPHONATE À LIAISON AMIDE ET LEURS UTILISATIONS
  申请人：UNIV FRASER SIMON

  公开号：WO2016199111A1

  公开（公告）日：2016-12-15

  The present invention relates to EP4 agonist-bisphosphonate conjugates or related compounds and uses thereof. Said conjugates or related compounds may be used to provide delivery of an EP4 agonist or related compound to a desired site of action, such as a bone. Bisphosphonate moieties, linked to the EP4 agonists via amide linkers, have been implicated in the inhibition of bone resorption and bone targeting.

  本发明涉及EP4激动剂-双膦酸酯共轭物或相关化合物及其用途。所述共轭物或相关化合物可用于将EP4激动剂或相关化合物传递至所需的作用部位，如骨骼。通过酰胺连接剂与EP4激动剂相连的双膦酸酯基团已被证实与抑制骨吸收和骨靶向有关。
• Dual-action EP4 agonist—bisphosphonate conjugates and uses thereof
  申请人：Simon Fraser University

  公开号：US09650414B1

  公开（公告）日：2017-05-16

  The invention provides in part, compounds according to Formula I: and uses thereof.

  这项发明部分提供了按照公式I的化合物及其用途。
• Amide-linked EP4 agonist-bisphosphonate compounds and uses thereof
  申请人：SIMON FRASER UNIVERSITY

  公开号：US10400000B2

  公开（公告）日：2019-09-03

  The present invention relates to conjugate compounds and methods of making and using same.

  本发明涉及共轭化合物及其制造和使用方法。
• PROSTAGLANDIN-BISPHOSPHONATE CONJUGATE COMPOUNDS, METHODS OF MAKING SAME, AND USES THEREOF
  申请人：Simon Fraser University

  公开号：US20130157984A1

  公开（公告）日：2013-06-20

  The invention provides in part, conjugate compounds. The invention also provides synthesis methods for making the compounds, and uses of the compounds.
• AMIDE-LINKED EP4 AGONIST-BISPHOSPHONATE COMPOUNDS AND USES THEREOF
  申请人：SIMON FRASER UNIVERSITY

  公开号：US20180170951A1

  公开（公告）日：2018-06-21

  The present invention relates to conjugate compounds and methods of making and using same.