N-(3,5-dichloropyridin-4-yl)-3,4,5-trimethoxybenzamide | 1349175-46-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(3,5-dichloropyridin-4-yl)-3,4,5-trimethoxybenzamide
• CAS: 1349175-46-7
• 化学式: C₁₅H₁₄Cl₂N₂O₄
• 分子量: 357.193
• InChiKey: KBHPCYJCMPMHOF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  69.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3,4,5-三甲氧基苯甲酸 在 氯化亚砜 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 29.0h， 生成 N-(3,5-dichloropyridin-4-yl)-3,4,5-trimethoxybenzamide
  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

• Potent PDE4 inhibitor activates AMPK and Sirt1 to induce mitochondrial biogenesis
  作者：Sung-Jun Park、Faiyaz Ahmad、Robert J. Bahde、Andrew Philp、Jeonghan Kim、Tianjiao Huang、Myung K. Kim、William C. Trenkle、Jay H. Chung

  DOI：10.1371/journal.pone.0253269

  日期：——

  AMP-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor. Activation of AMPK leads to a number of metabolic benefits, including improved mitochondrial function in skeletal muscle and lowering of serum glucose levels in type-2 diabetes models. However, direct activation of AMPK leads to cardiac enlargement, and an alternative strategy that activates AMPK without affecting the heart is needed. Inhibition of phosphodiesterase 4 (PDE4), which is poorly expressed in the human heart, activates AMPK in other tissues. In a screen to identify novel PDE4 inhibitors, we discovered compound CBU91, which is 5–10 fold more potent than rolipram, the best characterized PDE4 inhibitor. CBU91, like rolipram, is able to activate AMPK and Sirt1 and increase mitochondrial function in myotubes. These findings suggest that activation of AMPK in myotubes is a general property of PDE4 inhibition and that PDE4 inhibition may activate AMPK in metabolically relevant tissues without affecting the heart.

  AMP-激活蛋白激酶（AMPK）是一种在进化上保守的能量传感器。激活AMPK会带来许多代谢益处，包括改善骨骼肌线粒体功能和降低2型糖尿病模型中的血清葡萄糖水平。然而，直接激活AMPK会导致心脏增大，需要一种激活AMPK而不影响心脏的替代策略。磷酸二酯酶4（PDE4）的抑制剂可以激活AMPK，而人类心脏中PDE4的表达较低。在筛选新型PDE4抑制剂的过程中，我们发现了CBU91化合物，其比最佳特征化PDE4抑制剂rolipram更有效，效力提高了5-10倍。CBU91，像rolipram一样，能够激活AMPK和Sirt1，并增加肌管中的线粒体功能。这些发现表明，PDE4抑制剂激活肌管中的AMPK是一种普遍特性，并且PDE4抑制剂可能在代谢相关组织中激活AMPK而不影响心脏。