2-chloro-9-(pyridin-2-ylmethyl)-9H-purin-6-amine

• 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: 2-chloro-9-(pyridin-2-ylmethyl)-9H-purin-6-amine
• 英文别名: 2-Chloro-9-(pyridin-2-ylmethyl)purin-6-amine
• 化学式: C₁₁H₉ClN₆
• 分子量: 260.686
• InChiKey: OAJBEJALFJRACU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  82.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-(溴甲基)吡啶氢溴酸盐 、 2-氯-6-氨基嘌呤 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以58%的产率得到2-chloro-9-(pyridin-2-ylmethyl)-9H-purin-6-amine
  参考文献：
  名称：

  Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors

  摘要：

  To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound 3a (IC50 = 0.010 μM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, 3a bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 Å with Tyr748, which possibly interprets the 220-fold selectivity of 3a against PDE2A. Additionally, oral administration of compound 3a achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.

  DOI：

  10.1021/acs.jmedchem.0c01573

文献信息

• Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors
  作者：Yadan Huang、Xu-Nian Wu、Qian Zhou、Yinuo Wu、Dongxiao Zheng、Zhe Li、Lei Guo、Hai-Bin Luo

  DOI：10.1021/acs.jmedchem.0c01573

  日期：2020.12.24

  To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound 3a (IC50 = 0.010 μM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, 3a bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 Å with Tyr748, which possibly interprets the 220-fold selectivity of 3a against PDE2A. Additionally, oral administration of compound 3a achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.