(S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one
• 英文别名: 2-(4-{6-[(3s)-3,4-Dimethylpiperazin-1-Yl]-4-Methylpyridin-3-Yl}phenyl)-8-(Hydroxymethyl)quinazolin-4(3h)-One；2-[4-[6-[(3S)-3,4-dimethylpiperazin-1-yl]-4-methylpyridin-3-yl]phenyl]-8-(hydroxymethyl)-3H-quinazolin-4-one
• 化学式: C₂₇H₂₉N₅O₂
• 分子量: 455.56
• InChiKey: CFSYLGXBPQXCCL-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  81.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one 、 N,N-二乙基亚磷酰胺二叔丁酯 在 四氮唑 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 50.25h， 以98%的产率得到(S)-di-tert-butyl(2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-4-oxo-3,4-dihydroquinazolin-8-yl)methyl phosphate
  参考文献：
  名称：

  小鼠红细胞介导的药物分子的稀有异种生物磷酸化，但不是激酶底物。

  摘要：

  异种生物的磷酸化是罕见的，可能是由于对它的强烈进化压力。这种稀有性最近可能是有意设计的激酶底物类似物的结果，这种激酶底物类似物依赖于激酶催化的活化作用来形成磷酸化的活性药物。我们报告口服剂量的罐头聚合酶抑制剂后，在小鼠血浆样品中意外地观察到一种罕见的磷酸化代谢物，该罐头不应用作激酶底物，即（S）-2-（4-（6-（3,4-二甲基哌嗪） -1-基）-4-甲基吡啶-3-基）苯基）-8-（羟甲基）喹唑啉-4（3H）-1（AZ2381）。小鼠肝细胞中未产生磷酸化代谢产物。体外实验表明，在以肝素为抗凝剂的小鼠全血中发生了AZ2381的磷酸化，而在小鼠血浆中则没有。磷酸化的代谢物也在大鼠，狗和人的血液中产生，尽管产量低于小鼠。磷酸化需要二价金属离子，因为该反应被金属螯合剂EDTA抑制。用小鼠血液的不同细胞部分进行的进一步研究表明，AZ2381的磷酸化是由红细胞介导的，而白细胞则不会发生。当将无机18O

  DOI：

  10.1124/dmd.117.076869
• 作为产物：
  描述：

  2-氨基-3-羧基苯甲酸甲酯 在 lithium aluminium tetrahydride 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 copper dichloride 作用下， 以 四氢呋喃 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 正丁醇 为溶剂， 反应 14.17h， 生成 (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)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

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.
• Mouse Red Blood Cell–Mediated Rare Xenobiotic Phosphorylation of a Drug Molecule Not Intended to Be a Kinase Substrate
  作者：Chungang Gu、Shenghua Wen、Peter Doig、Eric Gangl、Xiaolan Zheng、Yanjun Wang、Jeffrey W. Johannes

  DOI：10.1124/dmd.117.076869

  日期：2017.12

  metabolite was also produced in rat, dog, and human blood, albeit at lower yields than in mouse. Divalent metal ions are required for the phosphorylation since the reaction is inhibited by the metal chelator EDTA. Further investigations with different cellular fractions of mouse blood revealed that the phosphorylation of AZ2381 was mediated by erythrocytes but did not occur with leukocytes. The levels

  异种生物的磷酸化是罕见的，可能是由于对它的强烈进化压力。这种稀有性最近可能是有意设计的激酶底物类似物的结果，这种激酶底物类似物依赖于激酶催化的活化作用来形成磷酸化的活性药物。我们报告口服剂量的罐头聚合酶抑制剂后，在小鼠血浆样品中意外地观察到一种罕见的磷酸化代谢物，该罐头不应用作激酶底物，即（S）-2-（4-（6-（3,4-二甲基哌嗪） -1-基）-4-甲基吡啶-3-基）苯基）-8-（羟甲基）喹唑啉-4（3H）-1（AZ2381）。小鼠肝细胞中未产生磷酸化代谢产物。体外实验表明，在以肝素为抗凝剂的小鼠全血中发生了AZ2381的磷酸化，而在小鼠血浆中则没有。磷酸化的代谢物也在大鼠，狗和人的血液中产生，尽管产量低于小鼠。磷酸化需要二价金属离子，因为该反应被金属螯合剂EDTA抑制。用小鼠血液的不同细胞部分进行的进一步研究表明，AZ2381的磷酸化是由红细胞介导的，而白细胞则不会发生。当将无机18O