Abstract
2-Hydroxy-4,6-diamino-[1,3,5]triazines are described which are a novel class of potent inhibitors of the VEGF-R2 (flk-1/KDR) tyrosine kinase. 4-(Benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-[1,3,5]triazin-2-ol (14d) exhibited low nanomolar potency in the in vitro enzyme inhibition assay (IC(50) = 18 nM) and submicromolar inhibitory activity in a KDR-induced MAP kinase autophosphorylation assay in HUVEC cells (IC(50) = 280 nM), and also demonstrated good in vitro selectivity against a panel of growth factor receptor tyrosine kinases. Further, 14d showed antiangiogenic activity in an aortic ring explant assay by blocking endothelial outgrowths in rat aortas with an IC(50) of 1 microM.
MeSH terms
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Angiogenesis Inhibitors / chemical synthesis*
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology
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Animals
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Aorta / drug effects
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Aorta / physiology
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Benzothiazoles
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Capillaries / drug effects
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Capillaries / physiology
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Cell Line
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Combinatorial Chemistry Techniques
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiology
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Humans
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Organ Culture Techniques
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Phosphorylation
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Rats
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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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Triazines / chemical synthesis*
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Triazines / chemistry
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Triazines / pharmacology
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Umbilical Veins / cytology
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / chemistry*
Substances
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4-(benzothiazol-6-ylamino)-6-(benzyl-isopropyl-amino)-(1,3,5)triazin-2-ol
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Angiogenesis Inhibitors
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Benzothiazoles
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Thiazoles
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Triazines
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Vascular Endothelial Growth Factor Receptor-2