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

• 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
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2016
• Subjects: pyrimidine derivative; capsule endoscope
• Online Access: https://hdl.handle.net/10356/81558; http://hdl.handle.net/10220/39573
• Institution: Nanyang Technological University

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.