9-[(3aR,4R,6R,6aR)-6-(dichlorophosphanyloxymethyl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]purin-6-amine | 1157870-78-4

• 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: 9-[(3aR,4R,6R,6aR)-6-(dichlorophosphanyloxymethyl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]purin-6-amine
• CAS: 1157870-78-4
• 化学式: C₁₂H₁₄Cl₂N₅O₅P
• 分子量: 410.153
• InChiKey: GZESUFNFLUXCQI-MDNDXATMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  9-[(3aR,4R,6R,6aR)-6-(dichlorophosphanyloxymethyl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]purin-6-amine 、 氯屈膦酸三正丁胺盐 在 三正丁胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.42h， 生成
  参考文献：
  名称：

  2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure

  摘要：

  Extracellular nucleotides can modify the production or drainage of the aqueous humor via activation of P2 receptors and therefore affect the intraocular pressure (IOP). We have synthesized slowly hydrolyzable nucleoside di- and triphosphate analogues, 1, and 8-14. Analogues 8-14 were completely resistant to hydrolysis by alkaline phosphatase over 30 min at 37 degrees C. In human blood serum, analogues 8-14 exhibited high stability, e.g., analogues 9 and 10-14 were only 15% and 0% degraded after 24 h, respectively. Moreover, analogues 8-14 were highly stable at pH 1.4 (t(1/2) 1 h-30 days). Analogues 8-14 were agonists of the P2Y(1) receptor (EC50 0.57-9.54 mu M). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC50 95.5 nM). Analogue 9 was more effective at reducing IOP than several common glaucoma drugs and represents a promising alternative to timolol maleate, which cannot be used for the treatment of patients suffering from asthma or cardiac problems.

  DOI：

  10.1021/jm100030u
• 作为产物：
  描述：

  2',3'-(methoxymethylidene)adenosine 在 1,8-双二甲氨基萘 、 三氯化磷 作用下， 以 磷酸三甲酯 为溶剂， 反应 0.83h， 生成 9-[(3aR,4R,6R,6aR)-6-(dichlorophosphanyloxymethyl)-2-methoxy-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]purin-6-amine
  参考文献：
  名称：

  水解稳定和选择性 P2Y1 受体激动剂的鉴定

  摘要：

  P2Y 核苷酸受体 (P2YRs) 是有吸引力的药物靶点。大多数作为药物提出的 P2YR 激动剂由核苷酸支架组成，但由于其化学和酶学不稳定性，它们的使用受到限制。为了鉴定候选药物，我们开发了不可水解的 P2YR 激动剂。我们合成了 ATP-β,γ-CH 2类似物2 – 4，并评估了它们在 P2Y 1,2,4,6受体上的化学和代谢稳定性和活性。类似物2 - 4展出吨1/2的胃液的pH 14.5-65ħ值。它们在 37°C 下对碱性磷酸酶完全耐受 30 分钟，并在人血清中缓慢水解（t 1/212.7–71.9 小时）。与 ATP 相比，类似物2 – 4几乎不被三磷酸核苷二磷酸水解酶 NTPDase1,2,3,8（<8% 水解）和核苷酸焦磷酸酶 NPP1,3（水解≤10%）水解。类似物2和4B是 P2Y 1 R 的选择性激动剂，EC 50 s 分别为 0.08 和 17.2 μM。这些特征使类似物2和4B

  DOI：

  10.1016/j.ejmech.2008.07.015

文献信息

• Identification of hydrolytically stable and selective P2Y1 receptor agonists
  作者：Shay E. Eliahu、Jean Camden、Joanna Lecka、Gary A. Weisman、Jean Sévigny、Sylvie Gélinas、Bilha Fischer

  DOI：10.1016/j.ejmech.2008.07.015

  日期：2009.4

  and enzymatic instabilities. To identify drug candidates, we developed non-hydrolyzable P2YR agonists. We synthesized ATP-β,γ-CH2 analogues 2–4, and evaluated their chemical and metabolic stabilities and activities at P2Y1,2,4,6 receptors. Analogues 2–4 exhibited t1/2 values of 14.5–65 h in gastric juice pH. They were completely resistant to alkaline phosphatase for 30 min at 37 °C and slowly hydrolyzed

  P2Y 核苷酸受体 (P2YRs) 是有吸引力的药物靶点。大多数作为药物提出的 P2YR 激动剂由核苷酸支架组成，但由于其化学和酶学不稳定性，它们的使用受到限制。为了鉴定候选药物，我们开发了不可水解的 P2YR 激动剂。我们合成了 ATP-β,γ-CH 2类似物2 – 4，并评估了它们在 P2Y 1,2,4,6受体上的化学和代谢稳定性和活性。类似物2 - 4展出吨1/2的胃液的pH 14.5-65ħ值。它们在 37°C 下对碱性磷酸酶完全耐受 30 分钟，并在人血清中缓慢水解（t 1/212.7–71.9 小时）。与 ATP 相比，类似物2 – 4几乎不被三磷酸核苷二磷酸水解酶 NTPDase1,2,3,8（<8% 水解）和核苷酸焦磷酸酶 NPP1,3（水解≤10%）水解。类似物2和4B是 P2Y 1 R 的选择性激动剂，EC 50 s 分别为 0.08 和 17.2 μM。这些特征使类似物2和4B
• 2-MeS-β,γ-CCl₂-ATP is a Potent Agent for Reducing Intraocular Pressure
  作者：Shay Eliahu、Alba Martín-Gil、María Jesús Perez de Lara、Jesús Pintor、Jean Camden、Gary A. Weisman、Joanna Lecka、Jean Sévigny、Bilha Fischer

  DOI：10.1021/jm100030u

  日期：2010.4.22

  Extracellular nucleotides can modify the production or drainage of the aqueous humor via activation of P2 receptors and therefore affect the intraocular pressure (IOP). We have synthesized slowly hydrolyzable nucleoside di- and triphosphate analogues, 1, and 8-14. Analogues 8-14 were completely resistant to hydrolysis by alkaline phosphatase over 30 min at 37 degrees C. In human blood serum, analogues 8-14 exhibited high stability, e.g., analogues 9 and 10-14 were only 15% and 0% degraded after 24 h, respectively. Moreover, analogues 8-14 were highly stable at pH 1.4 (t(1/2) 1 h-30 days). Analogues 8-14 were agonists of the P2Y(1) receptor (EC50 0.57-9.54 mu M). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC50 95.5 nM). Analogue 9 was more effective at reducing IOP than several common glaucoma drugs and represents a promising alternative to timolol maleate, which cannot be used for the treatment of patients suffering from asthma or cardiac problems.