Abstract
To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.
MeSH terms
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3T3 Cells
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Biological Availability
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Mice
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors*
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Solubility
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Structure-Activity Relationship
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Sunitinib
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Indoles
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Pyrroles
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Receptor, Platelet-Derived Growth Factor beta
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Vascular Endothelial Growth Factor Receptor-2
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Sunitinib