4-[1-(ethoxymethyl)-1H-indol-3-yl]-3-(3,4,5-trimethoxyphenyl)-1,5-dihydro-2H-pyrrole-2-one | 1038914-82-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4-[1-(ethoxymethyl)-1H-indol-3-yl]-3-(3,4,5-trimethoxyphenyl)-1,5-dihydro-2H-pyrrole-2-one
• 英文别名: 3-[1-(ethoxymethyl)indol-3-yl]-4-(3,4,5-trimethoxyphenyl)-1,2-dihydropyrrol-5-one
• CAS: 1038914-82-7
• 化学式: C₂₄H₂₆N₂O₅
• 分子量: 422.481
• InChiKey: QEIHPMKEVRZNEO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  71
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  乙醇 、 3-(3,4,5-trimethoxyphenyl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indol-3-yl)-1,5-dihydro-2H-pyrrole-2-one 在 盐酸 作用下， 反应 1.25h， 以45%的产率得到4-[1-(ethoxymethyl)-1H-indol-3-yl]-3-(3,4,5-trimethoxyphenyl)-1,5-dihydro-2H-pyrrole-2-one
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Novel 3-Aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as Vascular Endothelial Growth Factor Receptor (VEGF-R) Inhibitors

  摘要：

  In this study we report on the design, synthesis, and biological evaluation of pyrrole-2-one 2 to be a highly potent VEGF-R2/3 inhibitor with IC50 of 31/37 nM. The novel 3,4-diaryl-2H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1H-pyrrole-2,5-dione (maleimide) VEGFR2/3 inhibitor I indicating two H-bond ligand-protein interactions in the ATP pocket for the amide 2 but not for the isomer 3. Flexible synthetic routes to 3,4-diaxyl-2H-pyrrole-2-ones and structure - activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC50 values) are presented. Accordingly to the in vitro data, compounds 1 and 2 were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas 3 was determined to be significantly less active. Hence, the pyrrole-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.

  DOI：

  10.1021/jm8001185

文献信息

• [DE] CYCLISCHE AMIDVERBINDUNGEN, VERFAHREN ZU DEREN HERSTELLUNG UND IHRE VERWENDUNG<br/>[EN] CYCLIC AMIDE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF<br/>[FR] COMPOSÉS D'AMIDES CYCLIQUES, LEUR PROCÉDÉ DE PRODUCTION ET LEUR UTILISATION
  申请人：UNIV EBERHARD KARLS

  公开号：WO2009010542A1

  公开（公告）日：2009-01-22

  Die Erfindung betrifft cyclische Amidverbindungen der allgemeinen Formel (I), worin R1 und R2 in Anspruch 1 definiert sind. Die Erfindung betrifft ferner das Verfahren zur Herstellung der Verbindungen der Formel (I), pharmazeutische Mittel enthaltend wenigstens eine dieser Verbindungen sowie deren Verwendung zur Angiogenesehemmung und zur Prävention und/oder Therapie von mit Angiogenese assoziierten Krankheiten, insbesondere Krebserkrankungen.
• Design, Synthesis, and Biological Evaluation of Novel 3-Aryl-4-(1<i>H</i>-indole-3yl)-1,5-dihydro-2<i>H</i>-pyrrole-2-ones as Vascular Endothelial Growth Factor Receptor (VEGF-R) Inhibitors
  作者：Christian Peifer、Roland Selig、Katrin Kinkel、Dimitri Ott、Frank Totzke、Christoph Schächtele、Regina Heidenreich、Martin Röcken、Dieter Schollmeyer、Stefan Laufer

  DOI：10.1021/jm8001185

  日期：2008.7

  In this study we report on the design, synthesis, and biological evaluation of pyrrole-2-one 2 to be a highly potent VEGF-R2/3 inhibitor with IC50 of 31/37 nM. The novel 3,4-diaryl-2H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1H-pyrrole-2,5-dione (maleimide) VEGFR2/3 inhibitor I indicating two H-bond ligand-protein interactions in the ATP pocket for the amide 2 but not for the isomer 3. Flexible synthetic routes to 3,4-diaxyl-2H-pyrrole-2-ones and structure - activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC50 values) are presented. Accordingly to the in vitro data, compounds 1 and 2 were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas 3 was determined to be significantly less active. Hence, the pyrrole-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.