L-902688 | 634193-54-7

• 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: L-902688
• 英文别名: 2-Pyrrolidinone, 5-((1E,3R)-4,4-difluoro-3-hydroxy-4-phenyl-1-butenyl)-1-(6-(1H-tetrazol-5-yl)hexyl)-, (5R)-；(5R)-5-[(E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-1-[6-(2H-tetrazol-5-yl)hexyl]pyrrolidin-2-one
• CAS: 634193-54-7
• 化学式: C₂₁H₂₇F₂N₅O₂
• 分子量: 419.474
• InChiKey: WPTLQOYLIXWRNN-SLKVGHROSA-N

物化性质

• 溶解度：
  DMF:30.0(最大浓度 mg/mL);71.52(最大浓度 mM)DMSO:30.0(最大浓度 mg/mL);71.52(最大浓度 mM)乙醇:30.0(最大浓度 mg/mL);71.52(最大浓度 mM)乙醇:PBS (pH 7.2) (1:1):0.5(最大浓度 mg/mL);1.19(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  30
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  95
• 氢给体数：
  2
• 氢受体数：
  7

制备方法与用途

L-902688 是一种有效且选择性的口服活性EP4受体激动剂，其Ki值为0.38 nM，EC50值为0.6 nM。它对EP4的selectivity远超其他EP和类前列腺素受体4000倍以上。

反应信息

• 作为反应物：
  描述：

  L-902688 在 mercury(II) diacetate 、 N,N-二异丙基乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 27.5h， 生成 [4-[[5-[6-[(2R)-2-[(E,3R)-4,4-difluoro-3-hydroxy-4-phenylbut-1-enyl]-5-oxopyrrolidin-1-yl]hexyl]tetrazol-2-yl]methoxycarbonylamino]-1-hydroxy-1-phosphonobutyl]phosphonic 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

文献信息

• 1,5-distributed pyrrolid-2-one derivatives for use as ep4 receptor agonists in the teatment of eye diseases such as glaucoma
  申请人：Billot Xavier

  公开号：US20050239872A1

  公开（公告）日：2005-10-27

  This invention relates to potent selective agonists of the EP 4 subtype of prostaglandin E2 receptors of formula (1), their use or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of the patient.

  本发明涉及公式（1）的EP4型前列腺素E2受体的强效选择性激动剂，以及它们在治疗青光眼和其他与患者眼内压升高相关的疾病中的使用或配制。
• EP4 receptor agonist, compositions and methods thereof
  申请人：Billot Xavier

  公开号：US20090258918A1

  公开（公告）日：2009-10-15

  This invention relates to potent selective agonists of the EP 4 subtype of prostaglandin E2 receptors, their use or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of a patient.

  本发明涉及到前列腺素E2受体的EP4亚型的有效选择性激动剂，它们的使用或其制剂在治疗青光眼和其他与患者眼内压升高相关的疾病中应用。
• EP4 RECEPTOR AGONIST, COMPOSITIONS AND METHODS THEREOF
  申请人：Billot Xavier

  公开号：US20130317013A1

  公开（公告）日：2013-11-28

  This invention relates to potent selective agonists of the EP 4 subtype of prostaglandin E2 receptors, their use or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of a patient.

  本发明涉及到PGE2受体EP4亚型的强效选择性激动剂，以及它们在治疗青光眼和其他与患者眼内压升高有关的疾病中的使用或制剂。
• IMPROVED METHODS FOR TREATING ISCHEMIA
  申请人：Fate Therapeutics, Inc.

  公开号：EP3381456A1

  公开（公告）日：2018-10-03

  The invention provides compositions comprising stem and/or progenitor cells that have been treated to enhance the therapeutic properties of the cells for treating ischemia. In particular, the present invention relates to the use of stem and/or progenitor cells having enhanced therapeutic properties to treat an ischemic tissue, a tissue damaged by ischemia, or at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia.

  本发明提供了包含干细胞和/或祖细胞的组合物，这些干细胞和/或祖细胞经过处理，增强了治疗缺血的治疗特性。特别是，本发明涉及使用具有增强治疗特性的干细胞和/或祖细胞治疗缺血组织、因缺血而受损的组织或至少一种与缺血组织或因缺血而受损的组织相关的症状。
• Methods of treating ischemia
  申请人：FATE THERAPEUTICS, INC.

  公开号：US10111907B2

  公开（公告）日：2018-10-30

  The invention provides compositions comprising stem and/or progenitor cells that have been treated to enhance the therapeutic properties of the cells for treating ischemia. In particular, the present invention relates to the use of stem and/or progenitor cells having enhanced therapeutic properties to treat an ischemic tissue, a tissue damaged by ischemia, or at least one symptom associated with an ischemic tissue or a tissue damaged by ischemia.

  本发明提供了包含干细胞和/或祖细胞的组合物，这些干细胞和/或祖细胞经过处理，增强了治疗缺血的治疗特性。特别是，本发明涉及使用具有增强治疗特性的干细胞和/或祖细胞治疗缺血组织、因缺血而受损的组织或至少一种与缺血组织或因缺血而受损的组织相关的症状。