methyl 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propanoate | 1208460-15-4

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: methyl 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propanoate
• 英文别名: methyl 3-(1,3,5-trimethylpyrazol-4-yl)propanoate
• CAS: 1208460-15-4
• 化学式: C₁₀H₁₆N₂O₂
• mdl: MFCD13614357
• 分子量: 196.249
• InChiKey: UMSSKDLDIDBGOD-UHFFFAOYSA-N

物化性质

• 沸点：
  287.5±35.0 °C(Predicted)
• 密度：
  1.08±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  44.1
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propanoate 在 lithium hydroxide monohydrate 作用下， 以 甲醇 为溶剂， 反应 18.0h， 以85%的产率得到3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propanoic acid
  参考文献：
  名称：

  Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

  摘要：

  N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

  DOI：

  10.1021/jm500066b
• 作为产物：
  描述：

  乙酰丙酮 在 potassium carbonate 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.33h， 生成 methyl 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)propanoate
  参考文献：
  名称：

  Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

  摘要：

  N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.

  DOI：

  10.1021/jm500066b

文献信息

• Design and Synthesis of High Affinity Inhibitors of <i>Plasmodium falciparum</i> and <i>Plasmodium vivax N</i>-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)
  作者：Mark D. Rackham、James A. Brannigan、Kaveri Rangachari、Stephan Meister、Anthony J. Wilkinson、Anthony A. Holder、Robin J. Leatherbarrow、Edward W. Tate

  DOI：10.1021/jm500066b

  日期：2014.3.27

  N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization.