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

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.

• Authors: Erik L Meredith, Nello Mainolfi, Stephen Poor, Yubin Qiu, Karl Miranda, James Powers, Donglei Liu, Fupeng Ma, Catherine Solovay, Chang Rao, Leland Johnson, Nan Ji, Gerald Artman, Leo Hardegger, Shawn Hanks, Siyuan Shen, Amber Woolfenden, Elizabeth Fassbender, Jeremy M Sivak, Yiqin Zhang, Debby Long, Rosemarie Cepeda, Fang Liu, Vinayak P Hosagrahara, Wendy Lee, Peter Tarsa, Karen Anderson, Jason Elliott, Bruce Jaffee
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 23 Pg. 9273-86 (Dec 10 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26568411 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Protein Kinase Inhibitors
• Pyrimidines
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Administration, Oral
• Angiogenesis Inhibitors (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Animals
• Choroid (drug effects, pathology)
• Choroidal Neovascularization (drug therapy, pathology)
• Female
• Humans
• Intravitreal Injections
• Male
• Mice
• Mice, Inbred C57BL
• Protein Kinase Inhibitors (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Pyrimidines (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Rats
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)
• Wet Macular Degeneration (drug therapy, pathology)