Fulvene and fulvalene compounds that inhibit nicotinamide adenine dinucleotide phosphate (NADPH) oxidases for the treatment of ophthalmic diseases and disorders including the dry form of age-related macular degeneration.
- Lead compound candidate identified.
- Demonstrated positive effects in in vivo preclinical ocular models of retinal degeneration, oxygen-induced neovascularization, permeability and inflammation.
NADPH oxidase inhibitors are potential candidates for the treatment of the dry form of age-related macular degeneration (AMD). Approximately 10 million individuals in the U.S. have some form of AMD. The dry form of AMD, where the light sensitive cells of the macula slowly degenerate, is the most common form and accounts for approximately 90% of all cases of AMD. There are no approved drug therapies to treat dry AMD. In addition to macular degeneration, these compounds may be suitable for other diseases and disorders of the eye including diabetic retinopathy, uveitis, keratitis and allergic conjunctivitis.
Increased levels of reactive oxygen species (ROS), which result from oxidative stress, appear to contribute to certain pathologic conditions in the eye. In the Age-Related Eye Disease Study (AREDS), anti-oxidant nutritional supplements were shown to slow the progression of dry AMD. In addition, NADPH oxidase inhibition has been shown to reduce retinal neovascularization. Therefore, reducing ROS levels may be a viable therapeutic strategy for AMD, diabetic retinopathy and other ophthalmic conditions. These novel compounds inhibit NADPH oxidases and broadly reduce ROS generated via other cellular mechanisms. Specifically, the fulvenes/fulvalenes have been shown to inhibit the production of agiopoietin-2 (ang-2). These compounds have demonstrated retinal protection and reduced retinal neovascularization in preclinical studies.
A lead compound has been identified and validated in multiple preclinical ocular models.