1-ethyl-N'-3-(4-hydroxyphenyl)propanoyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 1-ethyl-N'-3-(4-hydroxyphenyl)propanoyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide
• 英文别名: VP3.63；1-ethyl-4-hydroxy-N'-[3-(4-hydroxyphenyl)propanoyl]-2-oxoquinoline-3-carbohydrazide
• 化学式: C₂₁H₂₁N₃O₅
• 分子量: 395.415
• InChiKey: AAXWZSLEMCYUCH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  119
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-乙基-1,2-二氢-4-羟基-2-氧代-3-喹啉羧酸乙酯 、 3-(4-羟基苯基)丙肼 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.05h， 以73%的产率得到1-ethyl-N'-3-(4-hydroxyphenyl)propanoyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbohydrazide
  参考文献：
  名称：

  Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases

  摘要：

  Glycogen synthase kinase 3 beta (GSK-3 beta) is a central target in several unmet diseases. To increase the specificity of GSK-3 beta inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3 beta activity. Design synthesis, structure activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3 beta are presented here. Furthermore, we show how allosteric binders may overcome the beta-catenin side effects associated with strong GSK-3 beta inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal it atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3 beta may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3 beta inhibition exhibits therapeutic effects.

  DOI：

  10.1021/acs.jmedchem.7b00395

文献信息

• Subtly Modulating Glycogen Synthase Kinase 3 β: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases
  作者：Valle Palomo、Daniel I. Perez、Carlos Roca、Cara Anderson、Natalia Rodríguez-Muela、Concepción Perez、Jose A. Morales-Garcia、Julio A. Reyes、Nuria E. Campillo、Ana M. Perez-Castillo、Lee L. Rubin、Lubov Timchenko、Carmen Gil、Ana Martinez

  DOI：10.1021/acs.jmedchem.7b00395

  日期：2017.6.22

  Glycogen synthase kinase 3 beta (GSK-3 beta) is a central target in several unmet diseases. To increase the specificity of GSK-3 beta inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3 beta activity. Design synthesis, structure activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3 beta are presented here. Furthermore, we show how allosteric binders may overcome the beta-catenin side effects associated with strong GSK-3 beta inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal it atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3 beta may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3 beta inhibition exhibits therapeutic effects.