1-(tert-butyl)-3-(3,5-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | 956025-95-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 1-(tert-butyl)-3-(3,5-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
• 英文别名: 1-Tert-butyl-3-[(3,5-difluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine
• CAS: 956025-95-9
• 化学式: C₁₆H₁₇F₂N₅
• 分子量: 317.341
• InChiKey: GFAVGLXIXAHTSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  69.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-(tert-butyl)-3-(3,5-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine 在 盐酸 、 甲酸 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 3-(3,5-difluorobenzyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  吡唑并嘧啶类似物对钙依赖性蛋白激酶1（CDPK1）的抑制作用可降低弓形虫中枢神经系统疾病的建立和复发。

  摘要：

  钙依赖性蛋白激酶1（CDPK1）是机会病原体弓形虫中的必需酶。CDPK1控制着多个过程，这些过程对于弓形虫的细胞内复制周期至关重要，包括粘附素的分泌，运动性，侵袭和流出。值得注意的是，CDPK1在ATP结合袋中包含一个小的甘氨酸守卫残基，使其对具有与该扩展的结合袋互补的大取代基的ATP竞争性抑制剂敏感。在这里，我们探索了一系列CDPK1的吡唑并嘧啶抑制剂的结构-活性关系，目的是提高对宿主酶的选择性，提高抗寄生虫的效力，并改善代谢稳定性。所得的铅化合物24表现出优异的酶抑制作用和对CDPK1的选择性，并在体外有效抑制了寄生虫的生长。化合物24也可有效治疗小鼠急性弓形体病，减少向中枢神经系统的扩散以及减少严重免疫受损的小鼠中慢性感染的再激活。这些发现为开发用于治疗中枢神经系统弓形体病的CDPK1小分子抑制剂提供了概念验证。

  DOI：

  10.1021/acs.jmedchem.7b01192
• 作为产物：
  描述：

  3,5-二氟苯乙酸 在 草酰氯 、 sodium hydride 、 碳酸氢钠 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 正己烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 1-(tert-butyl)-3-(3,5-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  Optimizing Small Molecule Inhibitors of Calcium-Dependent Protein Kinase 1 to Prevent Infection by Toxoplasma gondii

  摘要：

  Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a number of new derivatives of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogues in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low mu M EC50 values) were highly correlated and occurred in a CDPK1-specific manner. Chemical modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compounds with enhanced stability while retaining activity. Several of these more potent compounds were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compounds for treatment of toxoplasmosis and perhaps related parasitic diseases.

  DOI：

  10.1021/jm4001314

文献信息

• MODULATION OF PROTEIN TRAFFICKING
  申请人：Bulawa Christine Ellen

  公开号：US20100331297A1

  公开（公告）日：2010-12-30

  Compounds and compositions are provided for treatment or amelioration of one or more disorders characterized by defects in protein trafficking. A method of treating a disorder characterized by impaired protein trafficking includes administering to a subject or contacting a cell with a compound of Formula I: [formula here] or pharmaceutically acceptable salts or derivatives thereof.

  本发明提供用于治疗或改善由蛋白质运输缺陷所特征的一个或多个疾病的化合物和组合物。一种治疗由蛋白质运输受损所特征的疾病的方法包括向受试者施用或与细胞接触化合物I的药物或其药学上可接受的盐或衍生物。[公式在此]
• Compositions and methods for treating parasitic diseases
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US11208411B2

  公开（公告）日：2021-12-28

  Disclosed herein, inter alia, are compositions and methods for treating parasitic diseases.

  本文特别披露了治疗寄生虫病的组合物和方法。
• COMPOSITIONS AND METHODS FOR TREATING PARASITIC DISEASES
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20200291030A1

  公开（公告）日：2020-09-17

  Disclosed herein, inter alia, are compositions and methods for treating parasitic diseases.
• [EN] COMPOSITIONS AND METHODS FOR TREATING PARASITIC DISEASES<br/>[FR] COMPOSITIONS ET MÉTHODES POUR TRAITER LES PARASITOSES
  申请人：THE REGANTS OF THE UNIV OF CALIFORNIA

  公开号：WO2017161344A1

  公开（公告）日：2017-09-21

  Disclosed herein, inter alia, are compositions and methods for treating parasitic diseases.
• Optimizing Small Molecule Inhibitors of Calcium-Dependent Protein Kinase 1 to Prevent Infection by Toxoplasma gondii
  作者：Sebastian Lourido、Chao Zhang、Michael S. Lopez、Keliang Tang、Jennifer Barks、Qiuling Wang、Scott A. Wildman、Kevan M. Shokat、L. David Sibley

  DOI：10.1021/jm4001314

  日期：2013.4.11

  Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a number of new derivatives of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogues in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low mu M EC50 values) were highly correlated and occurred in a CDPK1-specific manner. Chemical modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compounds with enhanced stability while retaining activity. Several of these more potent compounds were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compounds for treatment of toxoplasmosis and perhaps related parasitic diseases.