2-(4-{[(4-carboxylphenyl)amino]carbonothioyl}-1-piperazinyl)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid | 1206482-70-3

• 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-carboxylphenyl)amino]carbonothioyl}-1-piperazinyl)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid
• 英文别名: 2-(4-{[(4-carboxyphenyl)amino]carbonothioyl}-1-piperazinyl)-8-ethyl-5-oxo-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid；2-[4-[(4-Carboxyphenyl)carbamothioyl]piperazin-1-yl]-8-ethyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid
• CAS: 1206482-70-3
• 化学式: C₂₂H₂₂N₆O₅S
• 分子量: 482.52
• InChiKey: GHHZUAIBQWHGDP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  171
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  4-羧基苯基异硫氰酸酯 、 吡哌酸 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以58%的产率得到2-(4-{[(4-carboxylphenyl)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

• 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.