1-benzyl-4-chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine | 1470290-91-5

• 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-benzyl-4-chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine
• 英文别名: 1-Benzyl-4-chloro-6-methylsulfanylpyrazolo[3,4-d]pyrimidine；1-benzyl-4-chloro-6-methylsulfanylpyrazolo[3,4-d]pyrimidine
• CAS: 1470290-91-5
• 化学式: C₁₃H₁₁ClN₄S
• 分子量: 290.776
• InChiKey: XCXIGEGIABTNFJ-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：
  0.15
• 拓扑面积：
  68.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-benzyl-4-chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine 、 环己胺 以 乙醇 为溶剂， 反应 12.0h， 以70%的产率得到1-benzyl-N-cyclohexyl-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
  参考文献：
  名称：

  探索特权吡唑并[3,4- d ]嘧啶支架周围的化学空间：寻求新型的T315I突变型Abl的变构抑制剂

  摘要：

  具有高水平分子多样性的吡唑并[3,4- d ]嘧啶文库已通过应用允许C3，N1，C4和C6取代的合成序列开发而成。对这种基于“特权支架”的化合物集合的酶促筛选，证实了在以目标为导向的合成为特征的领域中，以多样性为导向的方法的使用。实际上，几种化合物对选定的激酶表现出高活性（即Src，Abl wt和T315I突变形式），而且有趣的是，新化合物作为A315的T315I突变形式的变构抑制剂出现了，打开了大门。开发新型非竞争性Abl抑制剂（T315I）的新机会。

  DOI：

  10.1021/co500004e
• 作为产物：
  描述：

  2-(甲硫基)-4,6-二氯-5-嘧啶甲醛 在 偶氮二甲酸二异丙酯 、 一水合肼 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 5.0h， 生成 1-benzyl-4-chloro-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine
  参考文献：
  名称：

  探索特权吡唑并[3,4- d ]嘧啶支架周围的化学空间：寻求新型的T315I突变型Abl的变构抑制剂

  摘要：

  具有高水平分子多样性的吡唑并[3,4- d ]嘧啶文库已通过应用允许C3，N1，C4和C6取代的合成序列开发而成。对这种基于“特权支架”的化合物集合的酶促筛选，证实了在以目标为导向的合成为特征的领域中，以多样性为导向的方法的使用。实际上，几种化合物对选定的激酶表现出高活性（即Src，Abl wt和T315I突变形式），而且有趣的是，新化合物作为A315的T315I突变形式的变构抑制剂出现了，打开了大门。开发新型非竞争性Abl抑制剂（T315I）的新机会。

  DOI：

  10.1021/co500004e

文献信息

• A novel pyrazolo [3,4-d] pyrimidine, KKC080106, activates the Nrf2 pathway and protects nigral dopaminergic neurons
  作者：Ji Ae Lee、Hye Ri Kim、Hyo Jin Son、Nari Shin、Se Hee Han、Chan Seong Cheong、Dong Jin Kim、Onyou Hwang

  DOI：10.1016/j.expneurol.2020.113387

  日期：2020.10

  The transcription factor nuclear factor-erythroid 2-related factor-2 (Nrf2) is known to induce neuroprotective and anti-inflammatory effects and is considered to be an excellent molecular target for drugs related to neurodegenerative disease therapy. Nrf2 activators previously tested in clinical trials were electrophilic, causing adverse effects due to non-selective and covalent modification of cellular thiols. In order to circumvent this issue, we constructed and screened a chemical library consisting of 241 pyrazolo [3,4-d] pyrimidine derivatives and discovered a novel, non-electrophilic compound: 1-benzyl-6-(methylthio)-N-(1-phenylethyl)-1H-pyrazolo [3,4-d] pyrimidine-4-amine (KKC080106). KKC080106 was able to activate Nrf2 signaling as it increases the cellular levels of Nrf2, binds to the Nrf2 inhibitor protein Keap1, and causes the accumulation of nuclear Nrf2. We also observed an increase in the expression levels of Nrf2-dependent genes for antioxidative/neuroprotective enzymes in dopaminergic neuronal cells. In addition, in lipopolysaccharide-activated microglia, KKC080106 suppressed the generation of the proinflammatory markers, such as IL-1 beta, TNF-alpha, cyclooxygenase-2, inducible nitric oxide synthase, and nitric oxide, and inhibited the phosphorylation of kinases known to be involved in inflammatory signaling, such as I kappa B kinase, p38, JNK, and ERK. As a drug, KKC080106 exhibited excellent stability against plasma enzymes and a good safety profile, evidenced by no mortality after the administration of 2000 mg/kg body weight, and minimal inhibition of the hERG channel activity. Pharmacokinetic analysis revealed that KKC080106 has good bioavailability and enters the brain after oral and intravenous administration, in both rats and mice. In MPTP-treated mice that received KKC080106 orally, the compound blocked microglial activation, protected the nigral dopaminergic neurons from degeneration, and prevented development of the dopamine deficiency-related motor deficits. These results suggest that KKC080106 has therapeutic potential for neurodegenerative disorders such as Parkinson's disease.