8-(3-((3-hydroxybenzyl)(methyl)amino)propoxy)-5H-chromeno[2,3-b]pyridin-5-one | 213891-12-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 8-(3-((3-hydroxybenzyl)(methyl)amino)propoxy)-5H-chromeno[2,3-b]pyridin-5-one
• 英文别名: 7-{3-[(3-hydroxybenzyl)methylamino]propoxy}-9-oxa-1-azaanthracen-10-one；8-[3-[(3-Hydroxyphenyl)methyl-methylamino]propoxy]chromeno[2,3-b]pyridin-5-one
• CAS: 213891-12-4
• 化学式: C₂₃H₂₂N₂O₄
• 分子量: 390.439
• InChiKey: YAYPXSDAXPRXNR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  71.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  异氰酸庚酯 、 8-(3-((3-hydroxybenzyl)(methyl)amino)propoxy)-5H-chromeno[2,3-b]pyridin-5-one 在 sodium hydride 作用下， 以 甲苯 为溶剂， 反应 24.0h， 以74%的产率得到3-((methyl(3-((5-oxo-5H-chromeno[2,3-b]pyridin-8-yl)oxy)propyl)amino)methyl)phenyl heptylcarbamate
  参考文献：
  名称：

  脂肪酸酰胺水解酶（FAAH），乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）：氨基甲酸酯作为潜在的抗阿尔茨海默氏病病原体发展的网络化目标

  摘要：

  内源性大麻素系统的调节正在成为治疗神经退行性疾病的可行途径，参与神经保护和抗炎过程。特别地，通过FAAH抑制间接增强内源性大麻素信号传导至治疗水平可能有益于神经退行性疾病，例如阿尔茨海默氏病，有效预防或减慢疾病的发展。因此，在寻找更有效的阿尔茨海默氏病治疗方法中，本文将多目标导向的配体范式用于氨基甲酸酯的设计，该氨基甲酸酯能够同时靶向最近提出的内源性大麻素系统和经典的胆碱酯酶系统，并实现有效的双重治疗。 FAAH /胆碱酯酶抑制剂。在这两个合成的化合物系列中，9和19被确定为有效的双重FAAH / ChE抑制剂，具有均衡的纳摩尔活性。因此，9和19可被视为阿尔茨海默氏病治疗的新有希望的候选者。

  DOI：

  10.1021/acs.jmedchem.6b00609
• 作为产物：
  描述：

  间羟基苯甲醛 在 sodium tetrahydroborate 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 37.0h， 生成 8-(3-((3-hydroxybenzyl)(methyl)amino)propoxy)-5H-chromeno[2,3-b]pyridin-5-one
  参考文献：
  名称：

  Acetylcholinesterase Inhibitors:  Synthesis and Structure−Activity Relationships of ω-[N-Methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl Derivatives

  摘要：

  Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyxanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.

  DOI：

  10.1021/jm9810046

文献信息

• The First Dual ChE/FAAH Inhibitors: New Perspectives for Alzheimer's Disease?
  作者：Angela Rampa、Manuela Bartolini、Alessandra Bisi、Federica Belluti、Silvia Gobbi、Vincenza Andrisano、Alessia Ligresti、Vincenzo Di Marzo

  DOI：10.1021/ml200313p

  日期：2012.3.8

  The treatment of Alzheimer's disease (AD) still remains an area of significant unmet need, with drugs that only target the symptoms of the disease. Therefore, there is considerable need for disease-modifying therapies. The complex etiology of AD prompts scientists to develop multitarget strategies to combat causes and symptoms. To this aim, we designed, synthesized, and tested four new carbamates as dual cholinesterase-FAAH inhibitors. The dual activity of these compounds could lead to a potentially more effective treatment for the counteraction of AD progression, because they would allow regulation of both ACh and eCB signaling and improve neuronal transmission and/or counteract neuroinflammation.