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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2008-7-3
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pubmed:databankReference |
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pubmed:abstractText |
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 IC 50 of 31/37 nM. The novel 3,4-diaryl-2 H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1 H-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-2 H-pyrrole-2-ones and structure-activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC 50 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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1520-4804
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
10
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pubmed:volume |
51
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3814-24
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:18529047-Angiogenesis Inhibitors,
pubmed-meshheading:18529047-Cell Line,
pubmed-meshheading:18529047-Crystallography, X-Ray,
pubmed-meshheading:18529047-Drug Design,
pubmed-meshheading:18529047-Endothelial Cells,
pubmed-meshheading:18529047-Humans,
pubmed-meshheading:18529047-Hydrogen,
pubmed-meshheading:18529047-Indoles,
pubmed-meshheading:18529047-Models, Molecular,
pubmed-meshheading:18529047-Molecular Structure,
pubmed-meshheading:18529047-Protein Kinase Inhibitors,
pubmed-meshheading:18529047-Pyrroles,
pubmed-meshheading:18529047-Receptors, Vascular Endothelial Growth Factor,
pubmed-meshheading:18529047-Structure-Activity Relationship
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pubmed:year |
2008
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pubmed:articleTitle |
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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pubmed:affiliation |
Department of Pharmacy, Eberhard-Karls University, Auf der Morgenstelle 8, D-72076 Tübingen, Germany. Christian.Peifer@uni-tuebingen.de
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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