methyl 3,5-diamino-6-phenylpyrazine-2-carboxylate | 1135686-60-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: methyl 3,5-diamino-6-phenylpyrazine-2-carboxylate
• 英文别名: Methyl 3,5-diamino-6-phenyl-2-pyrazinecarboxylate
• CAS: 1135686-60-0
• 化学式: C₁₂H₁₂N₄O₂
• 分子量: 244.253
• InChiKey: RZQQKXJMUBTEJC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  盐酸胍 、 methyl 3,5-diamino-6-phenylpyrazine-2-carboxylate 在 sodium 作用下， 以 异丙醇 为溶剂， 生成 3,5-diamino-N-carbamimidoyl-6-phenylpyrazine-2-carboxamide;hydrochloride
  参考文献：
  名称：

  Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA)

  摘要：

  A known side-activity of the oral potassium-sparing diuretic drug amiloride is inhibition of the enzyme urokinase-type plasminogen activator (uPA, K-i = 7 mu M), a promising anticancer target. Several studies have demonstrated significant antitumor/metastasis properties for amiloride in animal cancer models and it would appear that these arise, at least in part, through inhibition of uPA. Selective optimization of amiloride's structure for more potent inhibition of uPA and loss of diuretic effects would thus appear as an attractive strategy towards novel anticancer agents. The following report is a preliminary structure-activity exploration of amiloride analogs as inhibitors of uPA. A key finding was that the well-studied 5-substituted analogs ethylisopropyl amiloride (EIPA) and hexamethylene amiloride (HMA) are approximately twofold more potent than amiloride as uPA inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.044
• 作为产物：
  描述：

  3,5-二氨基吡嗪-2-羧酸甲酯 在 N-碘代丁二酰亚胺 、 copper(l) iodide 、 四(三苯基膦)钯 作用下， 生成 methyl 3,5-diamino-6-phenylpyrazine-2-carboxylate
  参考文献：
  名称：

  Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA)

  摘要：

  A known side-activity of the oral potassium-sparing diuretic drug amiloride is inhibition of the enzyme urokinase-type plasminogen activator (uPA, K-i = 7 mu M), a promising anticancer target. Several studies have demonstrated significant antitumor/metastasis properties for amiloride in animal cancer models and it would appear that these arise, at least in part, through inhibition of uPA. Selective optimization of amiloride's structure for more potent inhibition of uPA and loss of diuretic effects would thus appear as an attractive strategy towards novel anticancer agents. The following report is a preliminary structure-activity exploration of amiloride analogs as inhibitors of uPA. A key finding was that the well-studied 5-substituted analogs ethylisopropyl amiloride (EIPA) and hexamethylene amiloride (HMA) are approximately twofold more potent than amiloride as uPA inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.044

文献信息

• 6-Substituted amiloride derivatives as inhibitors of the urokinase-type plasminogen activator for use in metastatic disease
  作者：Benjamin J. Buckley、Hiwa Majed、Ashraf Aboelela、Elahe Minaei、Longguang Jiang、Karen Fildes、Chen-Yi Cheung、Darren Johnson、Daniel Bachovchin、Gregory M. Cook、Mingdong Huang、Marie Ranson、Michael J. Kelso

  DOI：10.1016/j.bmcl.2019.126753

  日期：2019.12

  anti-cancer side-activities in multiple rodent models. These effects appear to arise, at least in part, through moderate inhibition of the urokinase-type plasminogen activator (uPA, Ki = 2.4 µM), a pro-metastatic trypsin-like serine protease that is upregulated in many aggressive solid malignancies. In applying the selective optimization of side-activity (SOSA) approach, a focused library of twenty two 6-substituted

  口服保钾利尿剂阿米洛利在多种啮齿动物模型中均显示出抗癌的副作用。这些作用似乎至少部分是通过适度抑制尿激酶型纤溶酶原激活剂（uPA，K i= 2.4 µM），一种在多种侵袭性实体恶性肿瘤中上调的促转移性胰蛋白酶样丝氨酸蛋白酶。在应用选择性优化的活性（SOSA）方法中，制备了22个6-取代的阿米洛利衍生物的聚焦库，其中有多个实例显示了nPA范围内的uPA抑制能力。X射线共晶体结构显示，相对于阿米洛利，效能的提高是由于附加的6个取代基对uPA的S1β亚位点的占用增加而引起的。领先的化合物显示出对相关胰蛋白酶样丝氨酸蛋白酶的高选择性，并且在大鼠中没有利尿剂或抗利尿剂的作用。在晚期肺转移的异种移植小鼠模型中，化合物15显示出抗转移作用。
• Synthesis and preliminary evaluation of amiloride analogs as inhibitors of the urokinase-type plasminogen activator (uPA)
  作者：Hayden Matthews、Marie Ranson、Joel D.A. Tyndall、Michael J. Kelso

  DOI：10.1016/j.bmcl.2011.09.044

  日期：2011.11

  A known side-activity of the oral potassium-sparing diuretic drug amiloride is inhibition of the enzyme urokinase-type plasminogen activator (uPA, K-i = 7 mu M), a promising anticancer target. Several studies have demonstrated significant antitumor/metastasis properties for amiloride in animal cancer models and it would appear that these arise, at least in part, through inhibition of uPA. Selective optimization of amiloride's structure for more potent inhibition of uPA and loss of diuretic effects would thus appear as an attractive strategy towards novel anticancer agents. The following report is a preliminary structure-activity exploration of amiloride analogs as inhibitors of uPA. A key finding was that the well-studied 5-substituted analogs ethylisopropyl amiloride (EIPA) and hexamethylene amiloride (HMA) are approximately twofold more potent than amiloride as uPA inhibitors. (C) 2011 Elsevier Ltd. All rights reserved.