Discovery of Oral VEGFR‑2 Inhibitors with Prolonged Ocular Retention That Are Efficacious in Models of Wet Age-Related Macular Degeneration

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 h...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-12, Vol.58 (23), p.9273-9286
Main Authors: Meredith, Erik L, Mainolfi, Nello, Poor, Stephen, Qiu, Yubin, Miranda, Karl, Powers, James, Liu, Donglei, Ma, Fupeng, Solovay, Catherine, Rao, Chang, Johnson, Leland, Ji, Nan, Artman, Gerald, Hardegger, Leo, Hanks, Shawn, Shen, Siyuan, Woolfenden, Amber, Fassbender, Elizabeth, Sivak, Jeremy M, Zhang, Yiqin, Long, Debby, Cepeda, Rosemarie, Liu, Fang, Hosagrahara, Vinayak P, Lee, Wendy, Tarsa, Peter, Anderson, Karen, Elliott, Jason, Jaffee, Bruce
Format: Article
Language:English
Subjects:
Administration, Oral
Angiogenesis Inhibitors - administration & dosage
Angiogenesis Inhibitors - chemistry
Angiogenesis Inhibitors - pharmacokinetics
Angiogenesis Inhibitors - therapeutic use
Animals
Choroid - drug effects
Choroid - pathology
Choroidal Neovascularization - drug therapy
Choroidal Neovascularization - pathology
Female
Humans
Intravitreal Injections
Male
Mice
Mice, Inbred C57BL
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - therapeutic use
Pyrimidines - administration & dosage
Pyrimidines - chemistry
Pyrimidines - pharmacokinetics
Pyrimidines - therapeutic use
Rats
Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
Wet Macular Degeneration - drug therapy
Wet Macular Degeneration - pathology
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b01227