Nan Ji

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 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.

The Discovery of (S)-1-(6-(3-((4-(1-(Cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-1H-inden-4-yl)pyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic Acid, a Soluble Guanylate Cyclase Activator Specifically Designed for Topical Ocular Delivery as a Therapy for Glaucoma

Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.

Chapter Twenty-Two - Recent Progress in Small-Molecule Agents Against Age-Related Macular Degeneration

Abstract Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in industrialized countries. Drusen and hyper- or hypopigmentation of the retinal pigment epithelium (RPE) are the characteristics of early AMD (also known as dry AMD). This asymptomatic abnormality of the RPE advances to two forms of AMD with a permanent loss of vision: geographic atrophy (GA) and/or choroidal neovascularization (CNV or also known as wet AMD). Although significant progress has been made in recent years for the treatment of wet AMD using intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is still a need for less invasive treatment options. Furthermore, unlike for wet AMD, there is currently no treatment available for dry AMD or GA. This review will cover three emerging therapeutic target classes of low molecular weight agents for AMD: anti-angiogenesis agents, visual cycle inhibitors, and complement pathway inhibitors.