Abstract
The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.
MeSH terms
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Administration, Oral
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Angiogenesis Inhibitors / administration & dosage
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Angiogenesis Inhibitors / chemistry*
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Angiogenesis Inhibitors / pharmacokinetics
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Angiogenesis Inhibitors / therapeutic use*
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Animals
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Choroid / drug effects
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Choroid / pathology
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Choroidal Neovascularization / drug therapy*
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Choroidal Neovascularization / pathology
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Female
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Humans
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Intravitreal Injections
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Male
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Mice
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Mice, Inbred C57BL
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use*
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Pyrimidines / administration & dosage
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Pyrimidines / chemistry
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Pyrimidines / pharmacokinetics
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Pyrimidines / therapeutic use
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Rats
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Wet Macular Degeneration / drug therapy*
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Wet Macular Degeneration / pathology
Substances
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Angiogenesis Inhibitors
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Protein Kinase Inhibitors
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Pyrimidines
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Vascular Endothelial Growth Factor Receptor-2