Abstract
7-Aminopyrazolo[1,5- a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships of the pyrazolo[1,5- a]pyrimidine nucleus led to a series of 6-(4- N, N'-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (<10 nM) and cellularly (<10 nM). In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED 50 = 1.4 mg/kg).
MeSH terms
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Animals
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Edema / drug therapy
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Edema / enzymology
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Female
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Male
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Mice
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Models, Molecular
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Molecular Structure
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Phenylurea Compounds / chemical synthesis*
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Phenylurea Compounds / chemistry
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Phenylurea Compounds / pharmacology*
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Phenylurea Compounds / therapeutic use
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyrazoles / therapeutic use
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Pyrimidines / therapeutic use
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / chemistry
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Receptor Protein-Tyrosine Kinases / metabolism*
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Structure-Activity Relationship
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Urea / chemistry
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Uterine Diseases / drug therapy
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Uterine Diseases / enzymology
Substances
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Urea
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Receptor Protein-Tyrosine Kinases