2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,2-d]pyrimidin-5-yl)-N-(4-morpholin-4-yl-phenyl)-acetamide | 1366000-33-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,2-d]pyrimidin-5-yl)-N-(4-morpholin-4-yl-phenyl)-acetamide
• 英文别名: 2-(1,3-dimethyl-2,4-dioxopyrrolo[3,2-d]pyrimidin-5-yl)-N-(4-morpholin-4-ylphenyl)acetamide
• CAS: 1366000-33-0
• 化学式: C₂₀H₂₃N₅O₄
• 分子量: 397.434
• InChiKey: WOLZAQMWHLQQJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  87.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1,3,4-三甲基尿嘧啶 在 硫酸 、 硝酸 、 potassium carbonate 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 、 锌 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.42h， 生成 2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,2-d]pyrimidin-5-yl)-N-(4-morpholin-4-yl-phenyl)-acetamide
  参考文献：
  名称：

  7-Substituted-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as antagonists of the transient receptor potential ankyrin 1 (TRPA1) channel: A promising approach for treating pain and inflammation

  摘要：

  The transient receptor potential ankyrin 1 (TRPA1) channel is activated by a series of by-products of oxidative/nitrative stress, produced under inflammatory conditions or in the case of tissue damage, thus generating inflammatory and neuropathic pain and neurogenic inflammatory responses. These findings have identified TRPA1 as an emerging opportunity for the design and synthesis of selective inhibitors as potential analgesic and antiinflammatory agents. Herein we present the synthesis and functional evaluation of a new series of 7-substituted-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives designed as TRPA1 antagonists. A small library of compounds has been built by the introduction of differently substituted N-7-phenylacetamide or N-7-[4-(substituted-phenyl)-thiazol-2-yl]acetamide chains. All the synthesized compounds were assayed to evaluate their ability to block acrolein-mediated activation of native human and rat TRPA1 channels employing a fluorometric calcium imaging assay. Our study led us to the identification of compound 3h which showed considerably improved potency (IC50 = 400 nM) against human TRPA1 with regard to some of the most representative antagonists previously reported and integrated in our screening program as reference compounds. In addition, 3h proved to maintain its efficacy toward rTRPA1, which designates it as a possible candidate for future evaluation of in vivo efficacy in rodent animal model of inflammatory and neuropathic pain. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.01.020

文献信息

• 7-Substituted-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as antagonists of the transient receptor potential ankyrin 1 (TRPA1) channel: A promising approach for treating pain and inflammation
  作者：Pier Giovanni Baraldi、Romeo Romagnoli、Giulia Saponaro、Mojgan Aghazadeh Tabrizi、Stefania Baraldi、Pamela Pedretti、Camilla Fusi、Romina Nassini、Serena Materazzi、Pierangelo Geppetti、Delia Preti

  DOI：10.1016/j.bmc.2012.01.020

  日期：2012.3

  The transient receptor potential ankyrin 1 (TRPA1) channel is activated by a series of by-products of oxidative/nitrative stress, produced under inflammatory conditions or in the case of tissue damage, thus generating inflammatory and neuropathic pain and neurogenic inflammatory responses. These findings have identified TRPA1 as an emerging opportunity for the design and synthesis of selective inhibitors as potential analgesic and antiinflammatory agents. Herein we present the synthesis and functional evaluation of a new series of 7-substituted-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives designed as TRPA1 antagonists. A small library of compounds has been built by the introduction of differently substituted N-7-phenylacetamide or N-7-[4-(substituted-phenyl)-thiazol-2-yl]acetamide chains. All the synthesized compounds were assayed to evaluate their ability to block acrolein-mediated activation of native human and rat TRPA1 channels employing a fluorometric calcium imaging assay. Our study led us to the identification of compound 3h which showed considerably improved potency (IC50 = 400 nM) against human TRPA1 with regard to some of the most representative antagonists previously reported and integrated in our screening program as reference compounds. In addition, 3h proved to maintain its efficacy toward rTRPA1, which designates it as a possible candidate for future evaluation of in vivo efficacy in rodent animal model of inflammatory and neuropathic pain. (C) 2012 Elsevier Ltd. All rights reserved.