9-butyl-6-{[(3,4-dichlorophenyl)methyl]amino}-9H-purine-2-carbonitrile | 1007555-89-6

• 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: 9-butyl-6-{[(3,4-dichlorophenyl)methyl]amino}-9H-purine-2-carbonitrile
• 英文别名: 9-butyl-6-[(3,4-dichlorophenyl)methylamino]purine-2-carbonitrile
• CAS: 1007555-89-6
• 化学式: C₁₇H₁₆Cl₂N₆
• 分子量: 375.26
• InChiKey: FSQIUURXINGUNK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  79.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  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 9-butyl-6-{[(3,4-dichlorophenyl)methyl]amino}-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

文献信息

• Development of Potent Purine-Derived Nitrile Inhibitors of the Trypanosomal Protease TbcatB
  作者：Jeremy P. Mallari、Anang A. Shelat、Terri Obrien、Conor R. Caffrey、Aaron Kosinski、Michele Connelly、Michael Harbut、Doron Greenbaum、James H. McKerrow、R. Kiplin Guy

  DOI：10.1021/jm070760l

  日期：2008.2.1

  Human African trypanosomiasis (HAT), a major health concern in sub-Saharan Africa, is caused by the protozoan parasite Trypanosoma brucei. Recent studies have shown that a cathepsin B like protease, TbcatB, is essential to the survival of T brucei in vitro (Mackey, Z. B.; O'Brien, T. C.; Greenbaum, D. C.; Blank, R. B.; McKerrow, J. H. J. Biol. Chem. 2004, 279, 48426-48433). Herein, we describe the first inhibitors of TbcatB, a series of purine nitriles. The compounds are potent trypanocides, killing the parasite with a high degree of selectivity over a panel of three human cell lines. In addition, a predictive model of trypanocidal activity was developed on the basis of potency against TbcatB and various calculated physical property descriptors.
• 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.