6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine | 1062159-33-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine
• 英文别名: Pyrazolo pyrimidine, 5v；[4-[6-(1H-indol-5-yl)-4-morpholin-4-ylpyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-pyridin-3-ylmethanone
• CAS: 1062159-33-4
• 化学式: C₂₈H₂₈N₈O₂
• 分子量: 508.583
• InChiKey: DPTZAZDLROZORV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  38
• 可旋转键数：
  4
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  105
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  烟酰氯 、 4-(6-(1H-indol-5-yl)-1-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)morpholine 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine
  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

• PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS
  申请人：Zask Arie

  公开号：US20080234262A1

  公开（公告）日：2008-09-25

  The present invention relates to Pyrazolopyrimidine Analogs, methods of making Pyrazolopyrimidine Analogs, compositions comprising a Pyrazolopyrimidine Analog, and methods for treating mTOR-related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog. The invention also relates to treating PI3K-related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog.

  本发明涉及吡唑吡嘧啶类似物，制备吡唑吡嘧啶类似物的方法，包含吡唑吡嘧啶类似物的组合物，以及治疗mTOR相关疾病的方法，包括向需要的受试者施用有效量的吡唑吡嘧啶类似物。该发明还涉及治疗PI3K相关疾病的方法，包括向需要的受试者施用有效量的吡唑吡嘧啶类似物。
• 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.