(+/-)-trans-2-[3-methoxy-4-(2-bromophenylthioethoxy)-5-(N-butyl-N-hydroxyureidyl)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (+/-)-trans-2-[3-methoxy-4-(2-bromophenylthioethoxy)-5-(N-butyl-N-hydroxyureidyl)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran
• 英文别名: 3-[2-[2-(2-bromophenyl)sulfanylethoxy]-3-methoxy-5-[(2S,5S)-5-(3,4,5-trimethoxyphenyl)oxolan-2-yl]phenyl]-1-butyl-1-hydroxyurea
• 化学式: C₃₃H₄₁BrN₂O₈S
• 分子量: 705.667
• InChiKey: ADGAICNUKKFKGZ-UIOOFZCWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  45
• 可旋转键数：
  15
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  133
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (+/-)-trans-2-[3-methoxy-4-(2-bromophenylthioethoxy)-5-(N-butyl-N-hydroxyureidyl)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran 在 magnesium monoperoxyphthalate hexahydrate 作用下， 以 乙腈 为溶剂， 反应 2.0h， 以67%的产率得到(+/-)-trans-2-[3-methoxy-4-(2-bromophenylsulfonylethoxy)-5-(N-butyl-N-hydroxyureidyl)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran
  参考文献：
  名称：

  (±)-trans-2-[3-Methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a Potent Dual 5-Lipoxygenase Inhibitor and Platelet-Activating Factor Receptor Antagonist

  摘要：

  By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid-and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.

  DOI：

  10.1021/jm980046r
• 作为产物：
  描述：

  2-溴硫代苯酚 在 三乙胺 、 calcium chloride 、 锌 作用下， 以 乙醇 为溶剂， 反应 34.0h， 生成 (+/-)-trans-2-[3-methoxy-4-(2-bromophenylthioethoxy)-5-(N-butyl-N-hydroxyureidyl)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran
  参考文献：
  名称：

  (±)-trans-2-[3-Methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N- hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a Potent Dual 5-Lipoxygenase Inhibitor and Platelet-Activating Factor Receptor Antagonist

  摘要：

  By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid-and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.

  DOI：

  10.1021/jm980046r

文献信息

• (±)-<i>trans</i>-2-[3-Methoxy-4-(4-chlorophenylthioethoxy)-5-(<i>N</i>-methyl-<i>N</i>- hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (CMI-392), a Potent Dual 5-Lipoxygenase Inhibitor and Platelet-Activating Factor Receptor Antagonist
  作者：Xiong Cai、Ralph T. Scannell、David Yaeger、Md. Sajjat Hussoin、David B. Killian、Changgeng Qian、Joseph Eckman、San-Bao Hwang、Lynn Libertine-Garahan、C. Grace Yeh、Stephen H. Ip、T. Y. Shen

  DOI：10.1021/jm980046r

  日期：1998.5.1

  By incorporating an N-hydroxyurea functionality onto diaryltetrahydrofurans, a novel series of compounds was investigated as dual 5-lipoxygenese (5-LO) inhibitor and platelet-activating factor (PAF) receptor antagonist. These dual functional compounds were evaluated in vitro for 5-LO inhibition in RBL cell extracts and human whole blood, and PAF receptor antagonism in a receptor binding assay. PAF-induced hemoconcentration and arachidonic acid-and TPA-induced ear edema in mice were used to determine in vivo activities. The structure-activity relationship analysis to define a preclinical lead is presented. (+/-)-trans-2-[3-methoxy-4-(4-chlorophenylthioethoxy)-5-(N-methyl-N-hydroxyureidyl)methylphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (40, CMI-392) was selected for further study. In the arachidonic acid-induced mouse ear edema model, 40 was more potent than either zileuton (a 5-LO inhibitor) or BN 50739 (a PAF receptor antagonist), and it demonstrated the same inhibitory effect as a physical combination of the latter two agents. These results suggest that a single compound which both inhibits leukotriene synthesis and blocks PAF receptor binding may provide therapeutic advantages over single-acting agents. The clinical development of compound 40 is in progress.