4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-methoxyphenyl acetate | 1349175-50-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚酯
• 英文名称: 4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-methoxyphenyl acetate
• 英文别名: [4-[(3,5-Dichloropyridin-4-yl)carbamoyl]-2-methoxyphenyl] acetate
• CAS: 1349175-50-3
• 化学式: C₁₅H₁₂Cl₂N₂O₄
• 分子量: 355.177
• InChiKey: NNUJDOLMAFGMSP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  77.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-乙酰氧基-3-甲氧基苯甲酸 在 氯化亚砜 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 29.0h， 生成 4-((3,5-dichloropyridin-4-yl)carbamoyl)-2-methoxyphenyl acetate
  参考文献：
  名称：

  Pharmacological Validation of Trypanosoma brucei Phosphodiesterases B1 and B2 as Druggable Targets for African Sleeping Sickness

  摘要：

  Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report, we describe our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei, the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 inhibitor piclamilast, and some of its analogues, show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei. We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any other human PDEs.

  DOI：

  10.1021/jm201148s

文献信息

• Pharmacological Validation of Trypanosoma brucei Phosphodiesterases B1 and B2 as Druggable Targets for African Sleeping Sickness
  作者：Nicholas D. Bland、Cuihua Wang、Craig Tallman、Alden E. Gustafson、Zhouxi Wang、Trent D. Ashton、Stefan O. Ochiana、Gregory McAllister、Kristina Cotter、Anna P. Fang、Lara Gechijian、Norman Garceau、Rajiv Gangurde、Ron Ortenberg、Mary Jo Ondrechen、Robert K. Campbell、Michael P. Pollastri

  DOI：10.1021/jm201148s

  日期：2011.12.8

  Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report, we describe our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei, the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 inhibitor piclamilast, and some of its analogues, show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei. We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any other human PDEs.