N-[2-(4-Phenoxy-benzyl)-3H-benzimidazol-5-yl]-methanesulfonamide

• 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-[2-(4-Phenoxy-benzyl)-3H-benzimidazol-5-yl]-methanesulfonamide
• 英文别名: n-[2-(4-Phenoxybenzyl)benzimidazol-5-yl]methanesulphonamide；N-[2-[(4-phenoxyphenyl)methyl]-3H-benzimidazol-5-yl]methanesulfonamide
• 化学式: C₂₁H₁₉N₃O₃S
• 分子量: 393.466
• InChiKey: YOUFPIVQKJMXMT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  92.5
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-[2-(4-Phenoxy-benzyl)-3H-benzimidazol-5-yl]-methanesulfonamide 、 碘甲烷 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以52%的产率得到N-Methyl-N-[2-(4-phenoxy-benzyl)-3H-benzoimidazol-5-yl]-methanesulfonamide
  参考文献：
  名称：

  NR2B选择性N-甲基-D-天冬氨酸拮抗剂：5-取代的苯并咪唑的合成与评价。

  摘要：

  两类5取代的苯并咪唑被确定为N-甲基-d-天冬氨酸（NMDA）受体NR2B亚型的有效拮抗剂。所选化合物与NMDA受体的NR2A，NR2C和NR2D亚型以及hERG通道活性和α（1）-肾上腺素结合相比显示出非常好的选择性。苯并咪唑37a在大鼠角叉菜胶诱导的机械性痛觉过敏试验中显示出色的活性，并且在狗中显示出良好的药代动力学行为。

  DOI：

  10.1021/jm030483s
• 作为产物：
  描述：

  4-苯氧基苯乙酸 、 N-(3,4-diaminophenyl)methanesulfonamide 在 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 N-[2-(4-Phenoxy-benzyl)-3H-benzimidazol-5-yl]-methanesulfonamide
  参考文献：
  名称：

  NR2B选择性N-甲基-D-天冬氨酸拮抗剂：5-取代的苯并咪唑的合成与评价。

  摘要：

  两类5取代的苯并咪唑被确定为N-甲基-d-天冬氨酸（NMDA）受体NR2B亚型的有效拮抗剂。所选化合物与NMDA受体的NR2A，NR2C和NR2D亚型以及hERG通道活性和α（1）-肾上腺素结合相比显示出非常好的选择性。苯并咪唑37a在大鼠角叉菜胶诱导的机械性痛觉过敏试验中显示出色的活性，并且在狗中显示出良好的药代动力学行为。

  DOI：

  10.1021/jm030483s

文献信息

• 2-BENZYL AND 2-HETEROARYL BENZIMIDAZOLE NMDA/NR2B ANTAGONISTS
  申请人：Merck & Co., Inc.

  公开号：EP1242076A1

  公开（公告）日：2002-09-25
• EP1242076A4
  申请人：——

  公开号：EP1242076A4

  公开（公告）日：2002-11-27
• US6316474B1
  申请人：——

  公开号：US6316474B1

  公开（公告）日：2001-11-13
• [EN] 2-BENZYL AND 2-HETEROARYL BENZIMIDAZOLE NMDA/NR2B ANTAGONISTS<br/>[FR] BENZIMIDAZOLES A SUBSTITUTION BENZYLE ET HETEROARYLE EN POSITION 2 ANTAGONISTES DE NMDA/NR2B
  申请人：MERCK & CO INC

  公开号：WO2001032174A1

  公开（公告）日：2001-05-10

  Novel benzimidazoles, substituted in the 2-position by substituted benzyl groups or heteroaryl groups are effective as NMDA NR2B antagonists and are useful for relieving pain.
• Mapping the high-affinity binding domain of 5-substituted benzimidazoles to the proximal N-terminus of the GluN2B subunit of the NMDA receptor
  作者：X-K Wee、K-S Ng、H-W Leung、Y-P Cheong、K-H Kong、F-M Ng、W Soh、Y Lam、C-M Low

  DOI：10.1111/j.1476-5381.2009.00549.x

  日期：2010.1

  Background and purpose:  N‐methyl‐D‐aspartate (NMDA) receptors represent an attractive drug target for the treatment of neurological and neurodegenerative disorders associated with glutamate‐induced excitotoxicity. The aim of this study was to map the binding domain of high affinity 5‐substituted benzimidazole derivatives [N‐2‐[(4‐benzylpiperidin‐1‐yl)methyl]benzimidazol‐5‐yl}methanesulphonamide (XK1) and N‐[2‐(4‐phenoxybenzyl)benzimidazol‐5‐yl]methanesulphonamide (XK2)] on the GluN2B subunit of the NMDA receptor.Experimental approach:  The pharmacological antagonistic profiles of XK1 and XK2 were assessed using in vitro rat primary cerebrocortical neurones and two‐electrode voltage clamp on Xenopus oocytes expressing heterologous GluN1/GluN2B receptors. Direct ligand binding was determined using the recombinant amino‐terminal domain (ATD) of GluN2B.Key results:  XK1 and XK2 effectively protected against NMDA‐induced excitotoxicity in rat primary cortical neurones. Low concentrations of XK1 (10 nM) and XK2 (1 nM) significantly reversed neuronal death. Both compounds failed to inhibit currents measured from oocytes heterologously expressing GluN1‐1a subunit co‐assembled with the ATD‐deleted GluN2B subunit. XK1 and XK2 showed specific binding to recombinant protein of GluN2B ATD with low nanomolar affinities. Several residues in the recombinant ATD of GluN2B were identified to be critical for conferring XK1 and XK2 sensitivity. The inhibitory effects of XK1 and XK2 were pH‐sensitive, being increased at acidic pH.Conclusions and implications:  These results demonstrate that XK1 and XK2 are effective neuroprotective agents in vitro and indicate that 5‐substituted benzimidazole derivatives inhibit GluN1/GluN2B receptors via direct binding to the ATD of the GluN2B subunit. These compounds represent valuable alternatives to the classical antagonist ifenprodil as pharmacological tools for studying GluN2B‐containing NMDA receptors.