硫酸氢(17β)-2,3-二羟基雌-1(10),2,4-三烯-17-酯 | 127406-10-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 硫酸氢(17β)-2,3-二羟基雌-1(10),2,4-三烯-17-酯
• 英文名称: 4-(4-methylpyridin-3-yl)benzaldehyde
• CAS: 127406-10-4
• 化学式: C₁₃H₁₁NO
• 分子量: 197.236
• InChiKey: PFRBLJOVRJXDBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  30
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  硫酸氢(17β)-2,3-二羟基雌-1(10),2,4-三烯-17-酯 、 2-amino-3-(hydroxymethyl)-benzamide 在 sodium hydrogensulfite 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 1.5h， 以22 mg的产率得到8-(hydroxymethyl)-2-(4-(4-methylpyridin-3-yl)phenyl)quinazolin-4(3H)-one
  参考文献：
  名称：

  Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology

  摘要：

  The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germ line mutations of several Wnt pathway components, such as Axin, APC, and beta-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARE)) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100 fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms.

  DOI：

  10.1021/ml5003663
• 作为产物：
  描述：

  对溴苯甲醛 、 4-甲基吡啶-3-硼酸 在 四(三苯基膦)钯 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.42h， 生成 硫酸氢(17β)-2,3-二羟基雌-1(10),2,4-三烯-17-酯
  参考文献：
  名称：

  Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology

  摘要：

  The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germ line mutations of several Wnt pathway components, such as Axin, APC, and beta-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARE)) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100 fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms.

  DOI：

  10.1021/ml5003663

文献信息

• Pyrimidinone Nicotinamide Mimetics as Selective Tankyrase and Wnt Pathway Inhibitors Suitable for in Vivo Pharmacology
  作者：Jeffrey W. Johannes、Lynsie Almeida、Bernard Barlaam、P. Ann Boriack-Sjodin、Robert Casella、Rosemary A. Croft、Allan P. Dishington、Lakshmaiah Gingipalli、Chungang Gu、Janet L. Hawkins、Jane L. Holmes、Tina Howard、Jian Huang、Stephanos Ioannidis、Steven Kazmirski、Michelle L. Lamb、Thomas M. McGuire、Jane E. Moore、Derek Ogg、Anil Patel、Kurt G. Pike、Timothy Pontz、Graeme R. Robb、Nancy Su、Haiyun Wang、Xiaoyun Wu、Hai-Jun Zhang、Yue Zhang、Xiaolan Zheng、Tao Wang

  DOI：10.1021/ml5003663

  日期：2015.3.12

  The canonical Wnt pathway plays an important role in embryonic development, adult tissue homeostasis, and cancer. Germ line mutations of several Wnt pathway components, such as Axin, APC, and beta-catenin, can lead to oncogenesis. Inhibition of the poly(ADP-ribose) polymerase (PARE)) catalytic domain of the tankyrases (TNKS1 and TNKS2) is known to inhibit the Wnt pathway via increased stabilization of Axin. In order to explore the consequences of tankyrase and Wnt pathway inhibition in preclinical models of cancer and its impact on normal tissue, we sought a small molecule inhibitor of TNKS1/2 with suitable physicochemical properties and pharmacokinetics for hypothesis testing in vivo. Starting from a 2-phenyl quinazolinone hit (compound 1), we discovered the pyrrolopyrimidinone compound 25 (AZ6102), which is a potent TNKS1/2 inhibitor that has 100 fold selectivity against other PARP family enzymes and shows 5 nM Wnt pathway inhibition in DLD-1 cells. Moreover, compound 25 can be formulated well in a clinically relevant intravenous solution at 20 mg/mL, has demonstrated good pharmacokinetics in preclinical species, and shows low Caco2 efflux to avoid possible tumor resistance mechanisms.