4,4′-(6-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三嗪类
• 英文名称: 4,4′-(6-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholine
• 英文别名: 4-[4-[6-Chloro-4-(trifluoromethyl)pyridin-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]morpholine；4-[4-[6-chloro-4-(trifluoromethyl)pyridin-3-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]morpholine
• 化学式: C₁₇H₁₈ClF₃N₆O₂
• 分子量: 430.817
• InChiKey: HXRQTGTWDIAOLJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  76.5
• 氢给体数：
  0
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  4,4′-(6-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholine 、 甲氧基胺盐酸盐 在 碳酸氢钠 作用下， 以 二甲基亚砜 为溶剂， 反应 6.0h， 以15%的产率得到5-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)-N-methoxy-4-(trifluoromethyl)pyridin-2-amine
  参考文献：
  名称：

  5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

  摘要：

  Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.

  DOI：

  10.1021/acs.jmedchem.7b00930
• 作为产物：
  描述：

  没货 在 盐酸 、 sodium nitrite 、 copper(l) chloride 作用下， 以 水 为溶剂， 反应 2.0h， 以47%的产率得到4,4′-(6-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine-2,4-diyl)dimorpholine
  参考文献：
  名称：

  5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

  摘要：

  Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.

  DOI：

  10.1021/acs.jmedchem.7b00930

文献信息

• 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology
  作者：Florent Beaufils、Natasa Cmiljanovic、Vladimir Cmiljanovic、Thomas Bohnacker、Anna Melone、Romina Marone、Eileen Jackson、Xuxiao Zhang、Alexander Sele、Chiara Borsari、Jürgen Mestan、Paul Hebeisen、Petra Hillmann、Bernd Giese、Marketa Zvelebil、Doriano Fabbro、Roger L. Williams、Denise Rageot、Matthias P. Wymann

  DOI：10.1021/acs.jmedchem.7b00930

  日期：2017.9.14

  Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.