N-{2-[(4-benzylpiperidin-1-yl)methyl]benzimidazol-5-yl}methanesulphonamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: N-{2-[(4-benzylpiperidin-1-yl)methyl]benzimidazol-5-yl}methanesulphonamide
• 英文别名: XK1；N-[2-(4-Benzyl-piperidin-1-ylmethyl)-3H-benzoimidazol-5-yl]-methanesulfonamide；N-[2-[(4-benzylpiperidin-1-yl)methyl]-3H-benzimidazol-5-yl]methanesulfonamide
• 化学式: C₂₁H₂₆N₄O₂S
• 分子量: 398.529
• InChiKey: WAUCNDQNILDAKL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  86.5
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-{2-[(4-benzylpiperidin-1-yl)methyl]benzimidazol-5-yl}methanesulphonamide 在 盐酸 作用下， 以 乙醚 为溶剂， 生成 N-{2-[(4-benzylpiperidin-1-yl)methyl]benzimidazol-5-yl}methanesulfonamide dihydrochloride
  参考文献：
  名称：

  Mapping the high-affinity binding domain of 5-substituted benzimidazoles to the proximal N-terminus of the GluN2B subunit of the NMDA receptor

  摘要：

  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.

  DOI：

  10.1111/j.1476-5381.2009.00549.x
• 作为产物：
  描述：

  2-氯甲基-6-硝基-1h-苯并[d]咪唑 在 palladium on carbon 、 氢气 、 sodium carbonate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 20.0~70.0 ℃ 、150.0 kPa 条件下， 反应 18.5h， 生成 N-{2-[(4-benzylpiperidin-1-yl)methyl]benzimidazol-5-yl}methanesulphonamide
  参考文献：
  名称：

  Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors

  摘要：

  In this study, novel specific PET radioligands containing the 4-(4-fluorobenzyl)piperidine moiety and selectively antagonistic for the NR2B subunit containing NMDA receptors were developed. Two antagonists, RGH-896 (1a) and 4-(4-fluorobenzyl)piperidinyl-1-methyl-2-benzimidazol-5-ol (2a), belonging to two different structural families, were radiolabeled by an aromatic nucleophilic radiofluorination followed by a reduction of the para-position carbonyl function. Radiotracers [F-18]1a, [F-18]2a or the pattern 4-(4-[(18)[F]-fluorobenzyl)piperidine ([(18)[F]6) demonstrated an identical in vivo behavior with high accumulation of radioactivity in bone and cartilage which would suggest a radiodefluorination of the radiotracers. The identification of metabolites from 6 by LC-MS-MS confirmed the significant degree of defluorination as a result of the in vivo hydroxylation in the benzyl ring. In conclusion, [(18)[F]1a or [(18)[F]2a are not suitable for imaging the NR2B NMDA receptors due to their poor brain penetration. We also argue for a cautious use of the radiolabeled pattern, 4-(4-[(18)[F]-fluorobenzyl)piperidine, to develop PET radiotracers.(C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.03.013

文献信息

• NR2B-Selective <i>N</i>-Methyl-<scp>d</scp>-aspartate Antagonists:  Synthesis and Evaluation of 5-Substituted Benzimidazoles
  作者：John A. McCauley、Cory R. Theberge、Joseph J. Romano、Susan B. Billings、Kenneth D. Anderson、David A. Claremon、Roger M. Freidinger、Rodney A. Bednar、Scott D. Mosser、Stanley L. Gaul、Thomas M. Connolly、Cindra L. Condra、Menghang Xia、Michael E. Cunningham、Bohumil Bednar、Gary L. Stump、Joseph J. Lynch、Alison Macaulay、Keith A. Wafford、Kenneth S. Koblan、Nigel J. Liverton

  DOI：10.1021/jm030483s

  日期：2004.4.1

  Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical

  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。
• 1,4 substituted piperidinyl NMDA/NR2B antagonists
  申请人：Merck & Co., Inc.

  公开号：US06476041B1

  公开（公告）日：2002-11-05

  Novel piperidinyl compounds substituted in the 1- and 4-positions are effective as NMDA NR2B antagonists useful for relieving pain.

  新型在1-和4-位置取代的哌啶基化合物作为NMDA NR2B拮抗剂，可用于缓解疼痛。
• 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.
• EP1235798A4
  申请人：——

  公开号：EP1235798A4

  公开（公告）日：2003-04-23
• 1,4 SUBSTITUTED PIPERIDINYL NMDA/NR2B ANTAGONISTS
  申请人：Merck & Co., Inc.

  公开号：EP1235798A1

  公开（公告）日：2002-09-04