(3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(3,3-difluorocyclobutyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide | 1374251-03-2

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(3,3-difluorocyclobutyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide
• CAS: 1374251-03-2
• 化学式: C₁₇H₂₀F₂N₆O₄
• 分子量: 410.38
• InChiKey: IIIWRIHKOGYKJF-JNIYBQFBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.74
• 重原子数：
  29.0
• 可旋转键数：
  3.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  126.41
• 氢给体数：
  2.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(3,3-difluorocyclobutyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 在 盐酸 作用下， 以 1,4-二氧六环 、 水 为溶剂， 以77%的产率得到(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-N-(3,3-difluorocyclobutyl)-3,4-dihydroxytetrahydrofuran-2-carboxamide
  参考文献：
  名称：

  Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening

  摘要：

  Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse ago fists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5' derivatives, we evaluated the performance of an agonist-bound A(2A) adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A(1)AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs.

  DOI：

  10.1021/jm300095s
• 作为产物：
  描述：

  3,3-二氟环丁胺 、 2',3'-isopropylideneadenosine-5'-carboxylic acid 在 吡啶 、 1,2-二氯乙烷 作用下， 生成 (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(3,3-difluorocyclobutyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide
  参考文献：
  名称：

  Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening

  摘要：

  Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse ago fists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5' derivatives, we evaluated the performance of an agonist-bound A(2A) adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A(1)AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs.

  DOI：

  10.1021/jm300095s