1-(3-chloro-5-(4-morpholin-4-ylphenyl)pyridin-4-yl)piperidine-4-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 1-(3-chloro-5-(4-morpholin-4-ylphenyl)pyridin-4-yl)piperidine-4-carboxamide
• 英文别名: 1-[3-Chloro-5-(4-morpholin-4-ylphenyl)pyridin-4-yl]piperidine-4-carboxamide；1-[3-chloro-5-(4-morpholin-4-ylphenyl)pyridin-4-yl]piperidine-4-carboxamide
• 化学式: C₂₁H₂₅ClN₄O₂
• 分子量: 400.908
• InChiKey: DXSCXUJTRFRNTF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  71.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  哌啶-4-甲酰胺 在 四(三苯基膦)钯 、 sodium carbonate 、 三乙胺 作用下， 以 N-甲基吡咯烷酮 、 水 、 乙腈 为溶剂， 反应 1.75h， 生成 1-(3-chloro-5-(4-morpholin-4-ylphenyl)pyridin-4-yl)piperidine-4-carboxamide
  参考文献：
  名称：

  Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen

  摘要：

  WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.

  DOI：

  10.1021/jm501436m

文献信息

• Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen
  作者：Aurélie Mallinger、Simon Crumpler、Mark Pichowicz、Dennis Waalboer、Mark Stubbs、Olajumoke Adeniji-Popoola、Bozena Wood、Elizabeth Smith、Ching Thai、Alan T. Henley、Katrin Georgi、William Court、Steve Hobbs、Gary Box、Maria-Jesus Ortiz-Ruiz、Melanie Valenti、Alexis De Haven Brandon、Robert TePoele、Birgitta Leuthner、Paul Workman、Wynne Aherne、Oliver Poeschke、Trevor Dale、Dirk Wienke、Christina Esdar、Felix Rohdich、Florence Raynaud、Paul A. Clarke、Suzanne A. Eccles、Frank Stieber、Kai Schiemann、Julian Blagg

  DOI：10.1021/jm501436m

  日期：2015.2.26

  WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.