Abstract
A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[ d]isoxazoles, incorporating a N, N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology
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Binding Sites
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Biological Availability
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Capillary Permeability / drug effects
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Cell Line
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Cell Line, Tumor
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Edema / drug therapy
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Female
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Humans
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Isoxazoles / chemical synthesis*
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Isoxazoles / pharmacokinetics
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Isoxazoles / pharmacology
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Mice
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Mice, Inbred BALB C
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Models, Molecular*
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NIH 3T3 Cells
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Oxazoles / chemical synthesis*
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Oxazoles / pharmacokinetics
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Oxazoles / pharmacology
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Phenylurea Compounds / chemical synthesis*
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Phenylurea Compounds / pharmacokinetics
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Phenylurea Compounds / pharmacology
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Phosphorylation
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Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
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Structure-Activity Relationship
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Uterus / blood supply
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Xenograft Model Antitumor Assays
Substances
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1-(4-(3-amino-7-methoxybenzo(d)isoxazol-4-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea
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Anti-Inflammatory Agents, Non-Steroidal
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Antineoplastic Agents
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Isoxazoles
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Oxazoles
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Phenylurea Compounds
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Receptors, Platelet-Derived Growth Factor
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Receptors, Vascular Endothelial Growth Factor