2-[1-(1-benzylpiperidin-4-yl)-4-morpholin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol | 1062159-23-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 2-[1-(1-benzylpiperidin-4-yl)-4-morpholin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol
• 英文别名: Pyrazolo pyrimidine, 5g；2-[1-(1-benzylpiperidin-4-yl)-4-morpholin-4-ylpyrazolo[3,4-d]pyrimidin-6-yl]phenol
• CAS: 1062159-23-2
• 化学式: C₂₇H₃₀N₆O₂
• 分子量: 470.574
• InChiKey: MATKXKBQRWTLGT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  79.5
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine 、 2-羟基苯硼酸 在 四(三苯基膦)钯 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.05h， 生成 2-[1-(1-benzylpiperidin-4-yl)-4-morpholin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol
  参考文献：
  名称：

  Discovery of Potent and Selective Inhibitors of the Mammalian Target of Rapamycin (mTOR) Kinase

  摘要：

  The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3K gamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC50 = 9 nM; PI3K alpha IC50 = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORCl (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.

  DOI：

  10.1021/jm9012642

文献信息

• Antiparasitic Agents Based On mTOR Inhibitors
  申请人：Pollastri Michael P.

  公开号：US20130296316A1

  公开（公告）日：2013-11-07

  Disclosed is the use of mammalian target of rapamycin (mTOR) and/or phosphoinositide-3-kinase (PI3K) inhibitors as antiparasitic drugs, particularly in those parasitic infections caused by trypanosomatid parasites Trypanosoma sp. and Leishmania sp.). These inhibitors are useful as trypanocides.
• Discovery of Potent and Selective Inhibitors of the Mammalian Target of Rapamycin (mTOR) Kinase
  作者：Pawel Nowak、Derek C. Cole、Natasja Brooijmans、Matthew G. Bursavich、Kevin J. Curran、John W. Ellingboe、James J. Gibbons、Irwin Hollander、YongBo Hu、Joshua Kaplan、David J. Malwitz、Lourdes Toral-Barza、Jeroen C. Verheijen、Arie Zask、Wei-Guo Zhang、Ker Yu

  DOI：10.1021/jm9012642

  日期：2009.11.26

  The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3K gamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC50 = 9 nM; PI3K alpha IC50 = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORCl (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.