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

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• 作者：Christian Peifer ; Roland Selig ; Katrin Kinkel ; Dimitri Ott ; Frank Totzke ; Christoph Scha&#x308 ; chtele ; Regina Heidenreich ; Martin Ro&#x308 ; cken ; Dieter Schollmeyer ; Stefan Laufer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：July 10, 2008
• 年：2008
• 卷：51
• 期：13
• 页码：3814 - 3824
• 全文大小：990K
• 年卷期：v.51,no.13(July 10, 2008)
• ISSN：1520-4804

文摘

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) VEGF-R2/3 inhibitor 1 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-diaryl-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.