A novel NRF2 activator designed for an ophthalmic solution

Oxidative stress is a major contributor to retinal degeneration in ocular neurodegenerative diseases, including glaucoma, where the loss of retinal ganglion cells (RGCs) leads to vision loss. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays pivotal roles in the cellular defense system against oxidative and xenobiotic stress, making NRF2 activation a promising therapeutic target for ocular neurodegenerative disorders. Covalent NRF2 activators have been extensively studied in clinical trials, leading to the approval of two drugs. However, no non-covalent NRF2- Kelch-like ECH-associated protein 1 (KEAP1) protein-protein interaction (PPI) inhibitors are currently in clinical development, despite their potential for selective and reversible KEAP1 inhibition with fewer side effects. In this study, to develop high potency compounds with suitable properties for an eye drop preparation, we modified the structure of known NRF2-KEAP1 PPI inhibitors. The newly identified compound, SLOS-1811-06 tR1, exhibited neuroprotective effects at concentrations ≥0.01 nM in a hypoxia-induced neurodegeneration model using human-induced pluripotent stem cell (hiPSC)-derived RGCs. It showed high aqueous solubility (21.04 ± 0.08 mg/mL), enabling easy formulation as an eye drop. One hour after a single topical dose of a 0.5% SLOS-1811-06 tR1 solution in rabbits, its concentration in the posterior retina/choroid was 4.4 ± 2.7 nM, exceeding the effective level observed in vitro. These findings highlight the potential of SLOS-1811-06 tR1 as a promising topical drug candidate for treating oxidative stress-related glaucoma.