2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(3',5'-difluorobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol | 1417334-71-4

• 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: 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(3',5'-difluorobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol
• 英文别名: (2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(3',5'-difluorobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol；2-[[4-(3,5-Difluorophenyl)phenyl]methylsulfanyl]-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,3,4-oxadiazole；2-[[4-(3,5-difluorophenyl)phenyl]methylsulfanyl]-5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,3,4-oxadiazole
• CAS: 1417334-71-4
• 化学式: C₂₃H₁₆F₂N₂O₃S
• 分子量: 438.454
• InChiKey: IUEJEHPLFBVXJH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  82.7
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1-溴-3,5-二氟苯 在 N-溴代丁二酰亚胺(NBS) 、 四(三苯基膦)钯 、 偶氮二异丁腈 、 sodium carbonate 、 sodium hydroxide 作用下， 以 四氯化碳 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 5.0h， 生成 2-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-5-(3',5'-difluorobiphenyl-4-ylmethylsulfanyl)-[1,3,4]oxadiazol
  参考文献：
  名称：

  Structure-based optimization of oxadiazole-based GSK-3 inhibitors

  摘要：

  Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases beta-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3 alpha and beta, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3 alpha and 17 nM for GSK-3 beta. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3 alpha over GSK-3 beta, with an IC50 of 35 nM for GSK-3 alpha. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.06.006

文献信息

• [DE] DERIVATE VON 2-BENZYLSULFANYL[1,3,4]-OXADIAZOL UND DEREN MEDIZINISCHE VERWENDUNG<br/>[EN] 2-BENZYLSULFANYL[1,3,4]-OXADIAZOLE DERIVATIVES, AND MEDICAL USE THEREOF<br/>[FR] DÉRIVÉS DE 2-BENZYLSULFANYL[1,3,4]OXADIAZOLE ET UTILISATION DESDITS DÉRIVÉS EN MÉDECINE
  申请人：UNIV DARMSTADT TECH

  公开号：WO2013007663A1

  公开（公告）日：2013-01-17

  Die vorliegende Erfindung betrifft Verbindungen, die als selektive Liganden der Glykogen Synthase Kinase 3 (GSK-3) wirken und für die Behandlung von GSK-3-vermittelten Erkrankungen verwendet werden können. Die erfindungsgemäßen Verbindungen wirken als Inhibitoren der Glykogen Synthase Kinase 3 (GSK-3).
• Structure-based optimization of oxadiazole-based GSK-3 inhibitors
  作者：Fabio Lo Monte、Thomas Kramer、Jiamin Gu、Martin Brodrecht、Johannes Pilakowski、Ana Fuertes、Juan Manuel Dominguez、Batya Plotkin、Hagit Eldar-Finkelman、Boris Schmidt

  DOI：10.1016/j.ejmech.2012.06.006

  日期：2013.3

  Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases beta-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3 alpha and beta, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3 alpha and 17 nM for GSK-3 beta. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3 alpha over GSK-3 beta, with an IC50 of 35 nM for GSK-3 alpha. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety. (C) 2012 Elsevier Masson SAS. All rights reserved.