N-[(3-bromophenyl)methyl]-2-chloro-7H-purin-6-amine | 1259314-99-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: N-[(3-bromophenyl)methyl]-2-chloro-7H-purin-6-amine
• CAS: 1259314-99-2
• 化学式: C₁₂H₉BrClN₅
• 分子量: 338.594
• InChiKey: HQZHLQFRAMXVEU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  66.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-[(3-bromophenyl)methyl]-2-chloro-7H-purin-6-amine 在 potassium carbonate 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 生成 6-((3-bromobenzyl)amino)-9-(3-hydroxypropyl)-9H-purine-2-carbonitrile
  参考文献：
  名称：

  Optimization of purine-nitrile TbcatB inhibitors for use in vivo and evaluation of efficacy in murine models

  摘要：

  There are currently only four clinical drugs available for treating human African trypanosomiasis (HAT), three of which were developed over 60 years ago. Despite years of effort, there has been relatively little progress towards identifying orally available chemotypes active against the parasite in vivo. Here, we report the lead optimization of a purine-nitrile scaffold that inhibits the essential TbcatB protease and its evaluation in murine models. A lead inhibitor that had potent activity against the trypanosomal protease TbcatB in vitro and cultured parasites ex vivo was optimized by rationally driven medicinal chemistry to an inhibitor that is orally available, penetrates the CNS, has a promising pharmacokinetic profile, and is non-toxic at 200 mg/kg in a repeat dosage study. Efficacy models using oral administration of this lead inhibitor showed a significantly increased survival time in Trypanosoma brucei brucei infected mice but little effect on Trypanosoma brucei rhodesiense infected mice. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.09.073
• 作为产物：
  描述：

  3-溴苄胺 、 2,6-二氯嘌呤 以 仲丁醇 为溶剂， 生成 N-[(3-bromophenyl)methyl]-2-chloro-7H-purin-6-amine
  参考文献：
  名称：

  选择性 TbcatB 抑制剂的结构导向开发

  摘要：

  锥虫组织蛋白酶 TbcatB 是寄生虫生存所必需的，是一个有吸引力的治疗目标。在此，我们报告了 TbcatB 抑制剂的结构引导开发，其具有相对于罗得沙因和人类组织蛋白酶 B 和 L 的特异性。测试了抑制剂的酶活性、杀锥虫活性和一般细胞毒性。这些数据在化学上验证了 TbcatB 作为药物靶点，并证明相对于锥虫和人类同源物，有可能有效和选择性地抑制 TbcatB。

  DOI：

  10.1021/jm900908p

文献信息

• Structure-Guided Development of Selective TbcatB Inhibitors
  作者：Jeremy P. Mallari、Anang A. Shelat、Aaron Kosinski、Conor R. Caffrey、Michele Connelly、Fangyi Zhu、James H. McKerrow、R. Kiplin Guy

  DOI：10.1021/jm900908p

  日期：2009.10.22

  target. Herein we report the structure-guided development of TbcatB inhibitors with specificity relative to rhodesain and human cathepsins B and L. Inhibitors were tested for enzymatic activity, trypanocidal activity, and general cytotoxicity. These data chemically validate TbcatB as a drug target and demonstrate that it is possible to potently and selectively inhibit TbcatB relative to trypanosomal

  锥虫组织蛋白酶 TbcatB 是寄生虫生存所必需的，是一个有吸引力的治疗目标。在此，我们报告了 TbcatB 抑制剂的结构引导开发，其具有相对于罗得沙因和人类组织蛋白酶 B 和 L 的特异性。测试了抑制剂的酶活性、杀锥虫活性和一般细胞毒性。这些数据在化学上验证了 TbcatB 作为药物靶点，并证明相对于锥虫和人类同源物，有可能有效和选择性地抑制 TbcatB。
• Optimization of purine-nitrile TbcatB inhibitors for use in vivo and evaluation of efficacy in murine models
  作者：Jeremy P. Mallari、Fangyi Zhu、Andrew Lemoff、Marcel Kaiser、Min Lu、Reto Brun、R. Kiplin Guy

  DOI：10.1016/j.bmc.2010.09.073

  日期：2010.12

  There are currently only four clinical drugs available for treating human African trypanosomiasis (HAT), three of which were developed over 60 years ago. Despite years of effort, there has been relatively little progress towards identifying orally available chemotypes active against the parasite in vivo. Here, we report the lead optimization of a purine-nitrile scaffold that inhibits the essential TbcatB protease and its evaluation in murine models. A lead inhibitor that had potent activity against the trypanosomal protease TbcatB in vitro and cultured parasites ex vivo was optimized by rationally driven medicinal chemistry to an inhibitor that is orally available, penetrates the CNS, has a promising pharmacokinetic profile, and is non-toxic at 200 mg/kg in a repeat dosage study. Efficacy models using oral administration of this lead inhibitor showed a significantly increased survival time in Trypanosoma brucei brucei infected mice but little effect on Trypanosoma brucei rhodesiense infected mice. (C) 2010 Elsevier Ltd. All rights reserved.