2-chloro-9-((6-(furan-2-yl)pyridin-2-yl)methyl)-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-((6-(furan-2-yl)pyridin-2-yl)methyl)-9H-purin-6-amine
• 英文别名: 2-Chloro-9-[[6-(furan-2-yl)pyridin-2-yl]methyl]purin-6-amine；2-chloro-9-[[6-(furan-2-yl)pyridin-2-yl]methyl]purin-6-amine
• 化学式: C₁₅H₁₁ClN₆O
• 分子量: 326.745
• InChiKey: AWNMESNEBXVLMN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  95.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-溴吡啶-2-甲醇 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 三溴化磷 、 potassium carbonate 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 2-chloro-9-((6-(furan-2-yl)pyridin-2-yl)methyl)-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

• 一种2-氯腺嘌呤衍生物、制备方法及应用
  申请人：中山大学

  公开号：CN112266386B

  公开（公告）日：2022-03-25

  本发明属于药物化学技术领域，具体涉及一种2‑氯腺嘌呤衍生物、制备方法及应用。本发明提供的2‑氯腺嘌呤衍生物对磷酸二酯酶8型具有良好的抑制作用，并且还有较好的肝微粒体稳定性和成药性质，可应用于制备治疗和/或预防与磷酸二酯酶8型相关疾病的药物中，具有较好的开发潜力，增加治疗磷酸二酯酶8型相关疾病药物的可选择范围。
• 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.