N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-(pyridin-4-yl)-N-(thiophen-2-ylmethyl)propanamide | 1418131-59-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃嘧啶类
• 英文名称: N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-(pyridin-4-yl)-N-(thiophen-2-ylmethyl)propanamide
• 英文别名: N-[(4-oxo-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-2-yl)methyl]-3-pyridin-4-yl-N-(thiophen-2-ylmethyl)propanamide
• CAS: 1418131-59-5
• 化学式: C₂₁H₂₂N₄O₃S
• 分子量: 410.497
• InChiKey: PDQOVVDBQCANCP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  112
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one 在 sodium azide 、 2-氯-1,3-二甲基氯化咪唑啉 、 三乙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 37.75h， 生成 N-((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)-3-(pyridin-4-yl)-N-(thiophen-2-ylmethyl)propanamide
  参考文献：
  名称：

  Identification of NVP-TNKS656: The Use of Structure–Efficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor

  摘要：

  Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.

  DOI：

  10.1021/jm400807n

文献信息

• 4-OXO-3,5,7,8-TETRAHYDRO-4H-PYRANO[4,3-D]PYRMINIDINYL COMPOUNDS FOR USE AS TANKYRASE INHIBITORS
  申请人：Novartis AG

  公开号：US20150210709A1

  公开（公告）日：2015-07-30

  The present invention provides for compounds of formula (I) wherein R 1 and R 2 are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer.

  本发明提供了公式（I）中R1和R2被定义的化合物。本发明还提供了包含公式（I）化合物的制药组合物和组合物，以及将这些化合物用作坦克酶抑制剂和治疗Wnt信号和坦克酶1和2信号相关疾病的用途，其中包括但不限于癌症。
• 4-OXO-3,5,7,8-TETRAHYDRO-4H-PYRANO {4,3-D} PYRMINIDINYL COMPOUNDS FOR USE AS TANKYRASE INHIBITORS
  申请人：Novartis AG

  公开号：EP2731951B1

  公开（公告）日：2015-08-19
• US9227982B2
  申请人：——

  公开号：US9227982B2

  公开（公告）日：2016-01-05