N'-(3-allyl-2-hydroxybenzylidene)-2-(4-(4-fluorobenzoyl)piperazin-1-yl)acetohydrazide | 1554475-57-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N'-(3-allyl-2-hydroxybenzylidene)-2-(4-(4-fluorobenzoyl)piperazin-1-yl)acetohydrazide
• 英文别名: N′-[[2-hydroxy-3-(2-propenyl)phenyl]methylene]-4-(4-fluorobenzoyl)-1-piperazineacetohydrazide；2-[4-(4-fluorobenzoyl)piperazin-1-yl]-N-[(2-hydroxy-3-prop-2-enylphenyl)methylideneamino]acetamide
• CAS: 1554475-57-8
• 化学式: C₂₃H₂₅FN₄O₃
• 分子量: 424.475
• InChiKey: QJXMWQOMYXEJMI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  85.2
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  邻丙烯基氧基苯甲醛 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 生成 N'-(3-allyl-2-hydroxybenzylidene)-2-(4-(4-fluorobenzoyl)piperazin-1-yl)acetohydrazide
  参考文献：
  名称：

  Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics

  摘要：

  Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development.

  DOI：

  10.1021/acs.jmedchem.5b00413

文献信息

• Removal of Metabolic Liabilities Enables Development of Derivatives of Procaspase-Activating Compound 1 (PAC-1) with Improved Pharmacokinetics
  作者：Howard S. Roth、Rachel C. Botham、Steven C. Schmid、Timothy M. Fan、Levent Dirikolu、Paul J. Hergenrother

  DOI：10.1021/acs.jmedchem.5b00413

  日期：2015.5.14

  Procaspase-activating compound 1 (PAC-1) is an o-hydroxy-N-acylhydrazone that induces apoptosis in cancer cells by chelation of labile inhibitory zinc from procaspase-3. PAC-1 has been assessed in a wide variety of cell culture experiments and in vivo models of cancer, with promising results, and a phase 1 clinical trial in cancer patients has been initiated (NCT02355535). For certain applications, however, the in vivo half-life of PAC-1 could be limiting. Thus, with the goal of developing a compound with enhanced metabolic stability, a series of PAC-1 analogues were designed containing modifications that systematically block sites of metabolic vulnerability. Evaluation of the library of compounds identified four potentially superior candidates with comparable anticancer activity in cell culture, enhanced metabolic stability in liver microsomes, and improved tolerability in mice. In head-to-head experiments with PAC-1, pharmacokinetic evaluation in mice demonstrated extended elimination half-lives and greater area under the curve values for each of the four compounds, suggesting them as promising candidates for further development.