Abstract
A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.
MeSH terms
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Administration, Oral
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Animals
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Chemistry, Pharmaceutical
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Drug Design
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Edema / pathology
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Estradiol / pharmacology
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Female
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Indenes / chemistry
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Indenes / pharmacology*
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Inhibitory Concentration 50
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Mice
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Models, Chemical
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Models, Molecular
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Structure-Activity Relationship
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Uterus / drug effects
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / chemistry
Substances
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Indenes
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Pyrazoles
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Vascular Endothelial Growth Factor A
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pyrazole
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Estradiol
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Vascular Endothelial Growth Factor Receptor-2