(R)-ethyl 4-(4-(3-methylmorpholino)-6-(4-(3-pyridin-4-ylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate | 1062172-24-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (R)-ethyl 4-(4-(3-methylmorpholino)-6-(4-(3-pyridin-4-ylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
• 英文别名: ethyl 4-[4-[(3R)-3-methylmorpholin-4-yl]-6-[4-(pyridin-4-ylcarbamoylamino)phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate
• CAS: 1062172-24-0
• 化学式: C₃₀H₃₅N₉O₄
• 分子量: 585.666
• InChiKey: KPXVSFMQOAWOEC-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  43
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  140
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-氨基吡啶 、 三光气 、 ethyl (R)-4-(6-(4-aminophenyl)-4-(3-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate 在 三乙胺 作用下， 生成 (R)-ethyl 4-(4-(3-methylmorpholino)-6-(4-(3-pyridin-4-ylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  Morpholine Derivatives Greatly Enhance the Selectivity of Mammalian Target of Rapamycin (mTOR) Inhibitors

  摘要：

  Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3K alpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961 Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.

  DOI：

  10.1021/jm901415x

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。
• [EN] PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS<br/>[FR] ANALOGUES DE PYRAZOLOPYRIMIDINE ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE KINASE MTOR ET KINASE PI3
  申请人：WYETH CORP

  公开号：WO2008115974A2

  公开（公告）日：2008-09-25

  [EN] 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.
  [FR] La présente invention concerne des analogues de pyrazolopyrimidine, des procédés de préparation d'analogues de pyrazolopyrimidine et des compositions comprenant un analogue de pyrazolopyrimidine et des procédés de traitement de troubles liés au mTOR comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'un analogue de pyrazolopyrimidine. L'invention concerne également le traitement de troubles liés au PI3K comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'un analogue de pyrazolopyrimidine.
• Morpholine Derivatives Greatly Enhance the Selectivity of Mammalian Target of Rapamycin (mTOR) Inhibitors
  作者：Arie Zask、Joshua Kaplan、Jeroen C. Verheijen、David J. Richard、Kevin Curran、Natasja Brooijmans、Eric M. Bennett、Lourdes Toral-Barza、Irwin Hollander、Semiramis Ayral-Kaloustian、Ker Yu

  DOI：10.1021/jm901415x

  日期：2009.12.24

  Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3K alpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961 Leu) accounts for the profound selectivity seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.