[5-[6-[(2R)-2-[(E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl]hexyl]tetrazol-1-yl]methyl (4-nitrophenyl) carbonate | 1350836-78-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: [5-[6-[(2R)-2-[(E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl]hexyl]tetrazol-1-yl]methyl (4-nitrophenyl) carbonate
• CAS: 1350836-78-0
• 化学式: C₂₉H₃₂F₂N₆O₇
• 分子量: 614.606
• InChiKey: UHEBGGSGRATREZ-DFDXVCEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  44
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  166
• 氢给体数：
  1
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  L-902688 、 碘甲基4-硝基苯基碳酸酯 在 mercury(II) diacetate 作用下， 以 乙腈 、 1,2-二氯乙烷 为溶剂， 反应 26.0h， 以66%的产率得到(5(6-((R)-2-((R,E)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl)-5-oxopyrrolidin-1-yl)hexyl)-2H-tetrazol-2-yl)methyl 4-nitrophenyl carbonate
  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

文献信息

• US9611284B2
  申请人：——

  公开号：US9611284B2

  公开（公告）日：2017-04-04
• [EN] PROSTAGLANDIN-BISPHOSPHONATE CONJUGATE COMPOUNDS, METHODS OF MAKING SAME, AND USES THEREOF<br/>[FR] COMPOSÉS CONJUGUÉS PROSTAGLANDINE-BISPHOSPHONATE, LEURS MÉTHODES DE FABRICATION ET LEURS UTILISATIONS
  申请人：UNIV FRASER SIMON

  公开号：WO2011147034A1

  公开（公告）日：2011-12-01

  The invention provides, in part, amino-bisphosphonate-prostaglandin conjugate compounds as well as methods for their synthesis. Said compounds may be used as EP4 agonist compounds in the prevention or treatment of conditions associated with abnormal or excessive bone loss, with abnormal or reduced bone resorption, or with abnormal calcium metabolism.
• Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis
  作者：Steve Arns、Romelo Gibe、Anne Moreau、M. Monzur Morshed、Robert N. Young

  DOI：10.1016/j.bmc.2012.01.024

  日期：2012.3

  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.