Abstract
Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
MeSH terms
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Adenosine Triphosphate / metabolism
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Caco-2 Cells
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Combinatorial Chemistry Techniques
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Drug Design
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Humans
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Indoles / pharmacology
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Molecular Structure
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Niacinamide / analogs & derivatives
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Niacinamide / pharmacology
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Oligonucleotides
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Phthalazines / pharmacology
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Pyridines / pharmacology
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology*
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Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Substances
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Indoles
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Oligonucleotides
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Phthalazines
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Pyridines
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Thiazoles
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Niacinamide
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vatalanib
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Adenosine Triphosphate
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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imetelstat