isosorbide-2-benzylcarbamate | 1072106-21-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 呋喃类
• 英文名称: isosorbide-2-benzylcarbamate
• 英文别名: 2-(benzylaminocarbonyloxy)-1,4:3,6-dianhydro-D-glucitol；2-(benzylaminocarbonyl)-1,4:3,6-dianhydro-D-glucitol；Isosorbide-2-benzyl carbamate；[(3R,3aR,6S,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] N-benzylcarbamate
• CAS: 1072106-21-8
• 化学式: C₁₄H₁₇NO₅
• 分子量: 279.293
• InChiKey: LYJZFQNPWOVWIJ-YVECIDJPSA-N

物化性质

• 熔点：
  76 °C
• 沸点：
  509.3±50.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  77
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  isosorbide-2-benzylcarbamate 在 5,5'-二硫双(2-硝基苯甲酸) 、 wild type human butyrylcholinesterase (EC 3.1.1.8) 、 (丙基碳酰基硫乙基)三甲基碘化铵 作用下， 生成 异山梨醇
  参考文献：
  名称：

  Isosorbide-2-benzyl Carbamate-5-salicylate, A Peripheral Anionic Site Binding Subnanomolar Selective Butyrylcholinesterase Inhibitor

  摘要：

  Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.

  DOI：

  10.1021/jm9014845
• 作为产物：
  描述：

  5-单硝酸异山梨酯 在 吡啶 、 palladium on activated carbon 、 氢气 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 生成 isosorbide-2-benzylcarbamate
  参考文献：
  名称：

  新型选择性丁酰胆碱酯酶抑制剂结合抗氧化剂功能作为阿尔茨海默氏病的潜在双峰疗法。

  摘要：

  异山梨醇-2-氨基甲酸酯-5-芳基酯是高效且选择性很高的丁酰胆碱酯酶抑制剂。本工作的目的是解决这样的假设，即异山梨醇-芳基-5-酯基团可以被抗氧化剂官能团取代，同时保持抑制剂的作用和选择性。我们成功地引入了阿魏酸或硫辛酸基团，产生了有效的丁酰胆碱酯酶（BuChE）选择性抑制剂。当用谷氨酸（5 mM）攻击细胞时，杂合化合物对小鼠海马HT-22细胞无毒，脂酸酯在10和25 µM时具有神经保护作用，与阳性对照槲皮素相似。氨基甲酸苄酯7a是BuChE的有效抑制剂（IC50 150 nM），在> 5 µM时可有效降低谷氨酸对神经元细胞的毒性。

  DOI：

  10.3390/molecules21040440

文献信息

• Isosorbide-2-carbamate Esters: Potent and Selective Butyrylcholinesterase Inhibitors
  作者：Ciaran G. Carolan、Gerald P. Dillon、Joanne M. Gaynor、Sean Reidy、Sheila A. Ryder、Denise Khan、Juan F. Marquez、John F. Gilmer

  DOI：10.1021/jm800564y

  日期：2008.10.23

  directly on the clinically used nitrate isosorbide mononitrate (ISMN) retention of the 5-nitrate group and introduction of a series of 2-carbamate functionalities. The compounds proved to be potent and selective inhibitors of human plasma butyrylcholinesterase ( huBuChE). In the second group, the nitrate ester was removed and replaced with a variety of alkyl and aryl esters. These generally exhibited nanomolar

  在这项研究中，我们报告了SAR和两组基于异山梨醇的胆碱酯酶抑制剂的特征。第一种直接基于临床上使用的硝酸硝酸异山梨酯一硝酸盐（ISMN）保留5-硝酸盐基团并引入一系列2-氨基甲酸酯官能团的方法。该化合物被证明是人血浆丁酰胆碱酯酶（huBuChE）的有效和选择性抑制剂。在第二组中，将硝酸酯除去并用各种烷基和芳基酯代替。这些通常表现出纳摩尔浓度的效力，对乙酰丁酰胆碱酯酶（AChE）具有较高的BuChE选择性。最有效和选择性最大的化合物是异山梨醇-2-苄基氨基甲酸酯-5-苯甲酸酯，对BuChE的IC 50为4.3 nM，选择性是人类红细胞AChE的> 50000倍。这些化合物的抑制作用是时间依赖性的，
• Isosorbide-based cholinesterase inhibitors; replacement of 5-ester groups leading to increased stability
  作者：Gerald P. Dillon、Joanne M. Gaynor、Denise Khan、Ciaran G. Carolan、Sheila A. Ryder、Juan F. Marquez、Sean Reidy、John F. Gilmer

  DOI：10.1016/j.bmc.2009.12.052

  日期：2010.2

  Isosorbide-2-carbamate-5-esters are highly potent and selective butyrylcholinesterase inhibitors with potential utility in the treatment of Alzheimer's Disease (AD). They are stable in human plasma but in mouse plasma they undergo hydrolysis at the 5-ester group potentially attenuating in vivo potency. In this paper we explore the role of the 5-position in modulating potency. The focus of the study was to increase metabolic stability while preserving potency and selectivity. Dicarbamates and 5-keto derivatives were markedly less potent than the ester class. The 2-benzylcarbamate-5-benzyl ether was found to be potent (IC50 52 nM) and stable in the presence of mouse plasma and liver homogenate. The compound produces sustained moderate inhibition of mouse butyrylcholinesterase at 1 mg/kg, IP. (C) 2009 Elsevier Ltd. All rights reserved.
• Isosorbide-2-benzyl Carbamate-5-salicylate, A Peripheral Anionic Site Binding Subnanomolar Selective Butyrylcholinesterase Inhibitor
  作者：Ciaran G. Carolan、Gerald P. Dillon、Denise Khan、Sheila A. Ryder、Joanne M. Gaynor、Sean Reidy、Juan F. Marquez、Mike Jones、Valerie Holland、John F. Gilmer

  DOI：10.1021/jm9014845

  日期：2010.2.11

  Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.
• Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer’s Disease
  作者：Mike Jones、Jun Wang、Shona Harmon、Beata Kling、Jörg Heilmann、John Gilmer

  DOI：10.3390/molecules21040440

  日期：——

  -aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid or lipoic acid groups producing potent selective inhibitors of butyrylcholinesterase

  异山梨醇-2-氨基甲酸酯-5-芳基酯是高效且选择性很高的丁酰胆碱酯酶抑制剂。本工作的目的是解决这样的假设，即异山梨醇-芳基-5-酯基团可以被抗氧化剂官能团取代，同时保持抑制剂的作用和选择性。我们成功地引入了阿魏酸或硫辛酸基团，产生了有效的丁酰胆碱酯酶（BuChE）选择性抑制剂。当用谷氨酸（5 mM）攻击细胞时，杂合化合物对小鼠海马HT-22细胞无毒，脂酸酯在10和25 µM时具有神经保护作用，与阳性对照槲皮素相似。氨基甲酸苄酯7a是BuChE的有效抑制剂（IC50 150 nM），在> 5 µM时可有效降低谷氨酸对神经元细胞的毒性。