Ac-Glu(OSU)-OBzl

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Ac-Glu(OSU)-OBzl
• 英文别名: Ac-Glu(OSu)-OBzl；1-O-benzyl 5-O-(2,5-dioxopyrrolidin-1-yl) (2S)-2-acetamidopentanedioate
• 化学式: C₁₈H₂₀N₂O₇
• 分子量: 376.366
• InChiKey: WNMFDDLILCORIX-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  27
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  119
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-((2R,3S)-7-fluoro-3-((S)-2-hydroxy-2-methyl-3-oxo-3-(2,2,3,3,3-pentafluoropropylamino)propanamido)-2-methyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5-(2H)-yl)ethyl 2-aminoethylcarbamate hydrochloride 、 Ac-Glu(OSU)-OBzl 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以83%的产率得到(S)-benzyl 2-acetamido-5-(2-((2-((2R,3S)-7-fluoro-3-((S)-2-hydroxy-2-methyl-3-oxo-3-(2,2,3,3,3-pentafluoropropylamino)propanamido)-2-methyl-4-oxo-3,4-dihydrobenzo[b][1,4]oxazepin-5-(2H)-yl)ethoxy)carbonylamino)ethylamino)-5-oxopentanoate
  参考文献：
  名称：

  [EN] TARGETED NOTCH PATHWAY INHIBITORS
  [FR] INHIBITEURS DE LA VOIE DE NOTCH CIBLÉE

  摘要：

  本发明涉及式(I)的新型共轭物：S - L - A (I)或其盐，其中A为γ-分泌酶抑制剂，L为连接子，S为肽酶特异性底物，以及它们的制备方法、包含它们的药物组合物及其作为药物，特别是用于治疗肾脏疾病和肾脏组织损伤的用途。

  公开号：

  WO2016198366A1

文献信息

• Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases
  作者：Lucienne Juillerat-Jeanneret、Alexander Flohr、Manfred Schneider、Isabelle Walter、Jean-Christophe Wyss、Rajesh Kumar、Dela Golshayan、Johannes D. Aebi

  DOI：10.1021/acs.jmedchem.5b00912

  日期：2015.10.22

  Notch is a membrane inserted protein activated by the membrane-inserted gamma-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the gamma-secretase inhibitor-based prodrugs 13a and 15a as substrates for gamma-glutamyltranspeptidase (gamma-CT) and/or gamma-glutamylcy-dotransferase (gamma-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-gamma-Glu-gamma-secretase inhibitor prodrug 13a (gamma-GT-targeting and gamma-GCT-targeting) but not from Ac-alpha-Glu-gamma-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the gamma-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notchl could be selectively down-regulated upon treatment with the Ac-gamma-Glu-gamma-secretase-inhibitor 13a.