LZP4 | 251963-82-3

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: LZP4
• 英文别名: 4-(3-Benzyloxyphenyl)-2,4-dioxo-butanoic acid；2,4-dioxo-4-(3-phenylmethoxyphenyl)butanoic acid
• CAS: 251963-82-3
• 化学式: C₁₇H₁₄O₅
• 分子量: 298.295
• InChiKey: FCBLTJFBERTVBY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  80.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  3-苄氧基苯乙酮 在 sodium hydroxide 、 sodium hydride 作用下， 以 1,4-二氧六环 、 甲苯 为溶剂， 反应 1.0h， 生成 LZP4
  参考文献：
  名称：

  Azido-Containing aryl β-Diketo acid HIV-1 integrase inhibitors

  摘要：

  Aryl beta-diketo acids (ADK) comprise a general class of potent HIV-1 integrase (IN) inhibitors, which can exhibit selective inhibition of strand transfer reactions in extracellular recombinant IN assays and provide potent antiviral effects in HIV-infected cells. Recent studies have shown that polycyclic aryl or aryl rings bearing aryl-containing substituents are components of potent members of this class. Reported herein is the first use of azido functionality as an aryl replacement in beta-diketo acid IN inhibitors. The ability of azido-containing inhibitors to exhibit potent inhibition of IN and antiviral protection in HIV-infected cells, renders the azide group of potential value in the further development of ADK-based IN inhibitors. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00059-3

文献信息

• [EN] HIV INTEGRASE INHIBITORS<br/>[FR] INHIBITEURS DE VIH INTEGRASE
  申请人：MERCK & CO., INC.

  公开号：WO1999062520A1

  公开（公告）日：1999-12-09

  (EN) Certain six-membered aromatic and heteroaromatic-dioxo-butyric acid derivatives are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.(FR) Cette invention a trait à certains dérivés d'acide dioxo-butyrique à 6 chaînons, aromatique et hétéro-aromatique, agissant en tant qu'inhibiteurs de VIH intégrase et de la réplication du VIH. Ces composés sont utilisés dans le cadre de la prévention et du traitement des infections par le VIH et du sida, que ce soit sous forme de composés, de sels acceptables du point de vue pharmaceutique ou d'ingrédients de composition pharmaceutique, seuls ou associés à d'autres antiviraux, immunorégulateurs, antibiotiques ou vaccins. L'invention concerne également des méthodes de traitement du sida ainsi que des méthodes de prévention et de traitement des infections par VIH.

  某些六元芳香和杂芳二酮丁酸衍生物被描述为HIV整合酶抑制剂和HIV复制抑制剂。这些化合物可用于预防或治疗HIV感染和治疗艾滋病，无论是作为化合物、药学上可接受的盐、药物组成成分，还是与其他抗病毒药物、免疫调节剂、抗生素或疫苗联合使用。还描述了治疗艾滋病的方法以及预防或治疗HIV感染的方法。
• Azido-Containing aryl β-Diketo acid HIV-1 integrase inhibitors
  作者：Xuechun Zhang、Godwin C.G Pais、Evguenia S Svarovskaia、Christophe Marchand、Allison A Johnson、Rajeshri G Karki、Marc C Nicklaus、Vinay K Pathak、Yves Pommier、Terrence R Burke

  DOI：10.1016/s0960-894x(03)00059-3

  日期：2003.3

  Aryl beta-diketo acids (ADK) comprise a general class of potent HIV-1 integrase (IN) inhibitors, which can exhibit selective inhibition of strand transfer reactions in extracellular recombinant IN assays and provide potent antiviral effects in HIV-infected cells. Recent studies have shown that polycyclic aryl or aryl rings bearing aryl-containing substituents are components of potent members of this class. Reported herein is the first use of azido functionality as an aryl replacement in beta-diketo acid IN inhibitors. The ability of azido-containing inhibitors to exhibit potent inhibition of IN and antiviral protection in HIV-infected cells, renders the azide group of potential value in the further development of ADK-based IN inhibitors. (C) 2003 Elsevier Science Ltd. All rights reserved.
• EP1082121A4
  申请人：——

  公开号：EP1082121A4

  公开（公告）日：2003-02-05
• HIV INTEGRASE INHIBITORS
  申请人：MERCK & CO., INC.

  公开号：EP1082121A1

  公开（公告）日：2001-03-14
• 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.