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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：58
• 期：23
• 页码：9273-9286
• 全文大小：560K
• ISSN：1520-4804

文摘

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鈥搕hroughput 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.