1-Methyl-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzimidazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-Methyl-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzimidazole
• 化学式: C₁₈H₂₁N₅
• 分子量: 307.398
• InChiKey: PFKBTYIOBXMJNI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  37.2
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氯甲基苯并咪唑 在 sodium hexamethyldisilazane 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.17h， 生成 1-Methyl-2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]benzimidazole
  参考文献：
  名称：

  Discovery of 2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (ABT-724), a Dopaminergic Agent with a Novel Mode of Action for the Potential Treatment of Erectile Dysfunction

  摘要：

  A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D-4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D-4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 mumol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D-4 selective agonism in this series of analogues.

  DOI：

  10.1021/jm030505a

文献信息

• The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2
  作者：Pier L. D’Alessandro、Corrado Corti、Adelheid Roth、Annarosa Ugolini、Anna Sava、Dino Montanari、Federica Bianchi、Stephen L. Garland、Ben Powney、Emma L. Koppe、Magalie Rocheville、Greg Osborne、Paloma Perez、Jesús de la Fuente、Maite De Los Frailes、Paul W. Smith、Clive Branch、David Nash、Stephen P. Watson

  DOI：10.1016/j.bmcl.2009.11.032

  日期：2010.1

  The optimisation of an HTS hit series (1) leading to the identification of structurally novel, selective, orally bioavailable mGluR2 positive modulators GSK1331258 and GSK1331268 is described. Structure-activity relationships, attenuation of dopaminergic activity, and potentiation of mGluR2 responses in rat hippocampal MPP-DG synapses are also reported. (C) 2009 Elsevier Ltd. All rights reserved.
• Discovery of 2-(4-Pyridin-2-ylpiperazin-1-ylmethyl)-1<i>H</i>-benzimidazole (ABT-724), a Dopaminergic Agent with a Novel Mode of Action for the Potential Treatment of Erectile Dysfunction
  作者：Marlon Cowart、Steven P. Latshaw、Pramila Bhatia、Jerome F. Daanen、Jeffrey Rohde、Sherry L. Nelson、Meena Patel、Teodozyi Kolasa、Masaki Nakane、Marie E. Uchic、Loan N. Miller、Marc A. Terranova、Renjie Chang、Diana L. Donnelly-Roberts、Marian T. Namovic、Peter R. Hollingsworth、Brenda R. Martino、James J. Lynch、James P. Sullivan、Gin C. Hsieh、Robert B. Moreland、Jorge D. Brioni、Andrew O. Stewart

  DOI：10.1021/jm030505a

  日期：2004.7.1

  A new class of agents with potential utility for the treatment of erectile dysfunction has been discovered, guided by the hypothesis that selective D-4 agonists are erectogenic but devoid of the side effects typically associated with dopaminergic agents. The lead agent 2-(4-pyridin-2-ylpiperazin-1-ylmethyl)-1H-benzimidazole (1, ABT-724) was discovered by optimization of a series of benzimidazole arylpiperazines. This highly selective D-4 agonist was found to be very potent and efficacious in vivo, eliciting penile erections in rats at a dose of 0.03 mumol/kg, with a positive response rate of 77% erectile incidence. Even at high doses, it was devoid of side effects in animal models of central nervous system behaviors, emesis, or nausea. The structure-activity relationship of the parent benzimidazole series leading to 1 is described, with the detailed in vitro and in vivo profiles described. Distinctive structural features were discovered that are associated with D-4 selective agonism in this series of analogues.