3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-(4-(2-phenylthiazol-4-yl)phenyl)propanamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-(4-(2-phenylthiazol-4-yl)phenyl)propanamide
• 化学式: C₂₆H₂₀N₄O₂S
• 分子量: 452.536
• InChiKey: WZLCIXBHINBDSH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.28
• 重原子数：
  33.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  87.74
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  3-(4-氧代-3,4-二氢-2-喹唑啉)-丙酸 、 4-(2-苯基-1,3-噻唑-4-基)苯胺 在 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-(4-(2-phenylthiazol-4-yl)phenyl)propanamide
  参考文献：
  名称：

  Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors

  摘要：

  Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.

  DOI：

  10.1021/jm401317z

文献信息

• Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
  作者：Zihao Hua、Howard Bregman、John L. Buchanan、Nagasree Chakka、Angel Guzman-Perez、Hakan Gunaydin、Xin Huang、Yan Gu、Virginia Berry、Jingzhou Liu、Yohannes Teffera、Liyue Huang、Bryan Egge、Renee Emkey、Erin L. Mullady、Steve Schneider、Paul S. Andrews、Lisa Acquaviva、Jennifer Dovey、Ankita Mishra、John Newcomb、Douglas Saffran、Randy Serafino、Craig A. Strathdee、Susan M. Turci、Mary Stanton、Cindy Wilson、Erin F. DiMauro

  DOI：10.1021/jm401317z

  日期：2013.12.27

  Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting β-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.