3-[(3,5-difluorophenyl)methyl]-2H-pyrazolo[3,4-d]pyrimidin-4-amine | 1428640-60-1

• 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: 3-[(3,5-difluorophenyl)methyl]-2H-pyrazolo[3,4-d]pyrimidin-4-amine
• CAS: 1428640-60-1
• 化学式: C₁₂H₉F₂N₅
• 分子量: 261.234
• InChiKey: LMUXQTZKPHTPNQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  80.5
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-[(3,5-difluorophenyl)methyl]-2H-pyrazolo[3,4-d]pyrimidin-4-amine 、 1-Boc-4-溴甲基哌啶 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 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 、 一水合肼 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 3-[(3,5-difluorophenyl)methyl]-2H-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

• 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.
• Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by <i>Toxoplasma gondii</i>
  作者：Florentine U. Rutaganira、Jennifer Barks、Mary Savari Dhason、Qiuling Wang、Michael S. Lopez、Shaojun Long、Joshua B. Radke、Nathaniel G. Jones、Amarendar R. Maddirala、James W. Janetka、Majida El Bakkouri、Raymond Hui、Kevan M. Shokat、L. David Sibley

  DOI：10.1021/acs.jmedchem.7b01192

  日期：2017.12.28

  structure–activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis

  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。