2-(4-{[(4-pyrazol-1-ylphenyl)amino]carbonothioyl}-1-piperazinyl)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid | 1206482-75-8

• 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: 2-(4-{[(4-pyrazol-1-ylphenyl)amino]carbonothioyl}-1-piperazinyl)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid
• 英文别名: 8-Ethyl-5-oxo-2-[4-[(4-pyrazol-1-ylphenyl)carbamothioyl]piperazin-1-yl]pyrido[2,3-d]pyrimidine-6-carboxylic acid
• CAS: 1206482-75-8
• 化学式: C₂₄H₂₄N₈O₃S
• 分子量: 504.572
• InChiKey: XUMOZWHFVMLFLM-UHFFFAOYSA-N

物化性质

• 沸点：
  715.9±70.0 °C(Predicted)
• 密度：
  1.49±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  152
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-(1H-吡唑-1-基)苯基异硫氰酸酯 、 吡哌酸 以 N,N-二甲基甲酰胺 为溶剂， 以94%的产率得到2-(4-{[(4-pyrazol-1-ylphenyl)amino]carbonothioyl}-1-piperazinyl)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid
  参考文献：
  名称：

  Optimization of a Pipemidic Acid Autotaxin Inhibitor

  摘要：

  Autotaxin (ATX, NPP2) has recently been shown to be the lysophospholipase D responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA). LPA has a well-established role in cancer, and the production of LPA is consistent with the cancer-promoting actions of ATX. Increased ATX and LPA receptor expression have been found in numerous cancer cell types. The current study has combined ligand-based computational approaches (binary quantitative structure-activity relationship), medicinal chemistry, and experimental enzymatic assays to optimize a previously identified small molecule ATX inhibitor, H2L 7905958 (1). Seventy prospective analogs were analyzed via computational screening, from which 30 promising compounds were synthesized and screened to assess efficacy, potency, and mechanism of inhibition. This approach has identified four analogs as potent as or more potent than the lead. The most potent analog displayed an IC50 of 900 nM with respect to ATX-mediated FS-3 hydrolysis with a K-i of 700 nM, making this compound approximately 3-fold more potent than the previously described lead.

  DOI：

  10.1021/jm9012328

文献信息

• PIPEMIDIC ACID DERIVATIVE AUTOTAXIN INHIBITORS
  申请人：Parrill-Baker Abby Louise

  公开号：US20120100592A1

  公开（公告）日：2012-04-26

  Novel and optimized classes of pipemidic acid derivative compounds that exhibit effective inhibition of autotaxin enzymes are provided. Such classes of compounds exhibit exhibit reactivity with autotaxin to ultimately reduce the size of the reactive sites thereon to prevent conversion of lysophosphatidyl choline to lysophophatidic acid. Furthermore, such compounds can be incorporated within delivery forms for human ingestion. As such, these compounds accord an excellent manner of potentially reducing generation of certain cancers attributable to the presence of naturally occurring autotaxin within the human body. Methods of inactivating autotaxin to certain degrees therewith such compounds are encompassed within invention as well.

  本发明提供了一种新型和优化的pipemidic酸衍生物类化合物，它们能够有效地抑制自体趋化素酶。这些化合物类别表现出与自体趋化素反应性，最终减小其上的反应性位点的大小，以防止溶血磷脂酰胆碱转化为溶血磷脂酸。此外，这些化合物可以被纳入人体摄入的递送形式中。因此，这些化合物为潜在地减少由于人体内天然存在的自体趋化素而导致某些癌症的产生提供了出色的方式。本发明还涵盖了使用这些化合物使自体趋化素在一定程度上失活的方法。
• US8497371B2
  申请人：——

  公开号：US8497371B2

  公开（公告）日：2013-07-30
• Optimization of a Pipemidic Acid Autotaxin Inhibitor
  作者：Adrienne B. Hoeglund、Heidi E. Bostic、Angela L. Howard、Irene W. Wanjala、Michael D. Best、Daniel L. Baker、Abby L. Parrill

  DOI：10.1021/jm9012328

  日期：2010.2.11

  Autotaxin (ATX, NPP2) has recently been shown to be the lysophospholipase D responsible for synthesis of the bioactive lipid lysophosphatidic acid (LPA). LPA has a well-established role in cancer, and the production of LPA is consistent with the cancer-promoting actions of ATX. Increased ATX and LPA receptor expression have been found in numerous cancer cell types. The current study has combined ligand-based computational approaches (binary quantitative structure-activity relationship), medicinal chemistry, and experimental enzymatic assays to optimize a previously identified small molecule ATX inhibitor, H2L 7905958 (1). Seventy prospective analogs were analyzed via computational screening, from which 30 promising compounds were synthesized and screened to assess efficacy, potency, and mechanism of inhibition. This approach has identified four analogs as potent as or more potent than the lead. The most potent analog displayed an IC50 of 900 nM with respect to ATX-mediated FS-3 hydrolysis with a K-i of 700 nM, making this compound approximately 3-fold more potent than the previously described lead.