tert-butyl 4-(4-(3-(benzyloxy)phenyl)-2,4-dioxobutanoyl)piperazine-1-carboxylate | 1092460-26-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: tert-butyl 4-(4-(3-(benzyloxy)phenyl)-2,4-dioxobutanoyl)piperazine-1-carboxylate
• 英文别名: LZP70；Tert-butyl 4-[2,4-dioxo-4-(3-phenylmethoxyphenyl)butanoyl]piperazine-1-carboxylate
• CAS: 1092460-26-8
• 化学式: C₂₆H₃₀N₂O₆
• 分子量: 466.534
• InChiKey: CXPIDSAUTBETCN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  93.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  N-Boc-哌嗪 、 LZP4 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 四氢呋喃 为溶剂， 反应 12.5h， 以47%的产率得到tert-butyl 4-(4-(3-(benzyloxy)phenyl)-2,4-dioxobutanoyl)piperazine-1-carboxylate
  参考文献：
  名称：

  Targeting Inactive Enzyme Conformation: Aryl Diketoacid Derivatives as a New Class of PTP1B Inhibitors

  摘要：

  There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.

  DOI：

  10.1021/ja8068177

文献信息

• Targeting Inactive Enzyme Conformation: Aryl Diketoacid Derivatives as a New Class of PTP1B Inhibitors
  作者：Sijiu Liu、Li-Fan Zeng、Li Wu、Xiao Yu、Ting Xue、Andrea M. Gunawan、Ya-Qiu Long、Zhong-Yin Zhang

  DOI：10.1021/ja8068177

  日期：2008.12.17

  There has been considerable interest in protein tyrosine phosphatase 1B (PTP1B) as a therapeutic target for diabetes, obesity, as well as cancer. Identifying inhibitory compounds with good bioavailability is a major challenge of drug discovery programs targeted toward PTPs. Most current PTP active site-directed pharmacophores are negatively charged pTyr mimetics which cannot readily enter the cell. This lack of cell permeability limits the utility of such compounds in signaling studies and further therapeutic development. We identify aryl diketoacids as novel pTyr surrogates and show that neutral amide-linked aryl diketoacid dimers also exhibit excellent PTP inhibitory activity. Kinetic studies establish that these aryl diketoacid derivatives act as noncompetitive inhibitors of PTP1B. Crystal structures of ligand-bound PTP1B reveal that both the aryl diketoacid and its dimeric derivative bind PTP1B at the active site, albeit with distinct modes of interaction, in the catalytically inactive, WPD loop open conformation. Furthermore, dimeric aryl diketoacids are cell permeable and enhance insulin signaling in hepatoma cells, suggesting that targeting the inactive conformation may provide a unique opportunity for creating active site-directed PTP1B inhibitors with improved pharmacological properties.