A novel NRF2 activator designed for an ophthalmic solution

Area of Science:

• Ophthalmology
• Neuroscience
• Pharmacology

Background:

• Oxidative stress significantly contributes to retinal degeneration in diseases like glaucoma, causing vision loss through retinal ganglion cell (RGC) death.
• Nuclear factor erythroid 2-related factor 2 (NRF2) is crucial for cellular defense against oxidative stress, making its activation a therapeutic strategy for neurodegenerative eye disorders.
• While covalent NRF2 activators are approved, non-covalent inhibitors targeting the NRF2-KEAP1 interaction are underexplored despite potential for safer, reversible inhibition.

Purpose of the Study:

• To develop novel non-covalent NRF2-KEAP1 protein-protein interaction (PPI) inhibitors with properties suitable for topical eye drop formulation.
• To evaluate the neuroprotective efficacy and pharmacokinetic profile of a lead compound, SLOS-1811-06 tR1, for treating oxidative stress-related glaucoma.

Main Methods:

• Modification of known NRF2-KEAP1 PPI inhibitors to create new compounds with enhanced potency and drug-like properties.
• Assessment of neuroprotective effects of SLOS-1811-06 tR1 in a human-induced pluripotent stem cell (hiPSC)-derived RGC model of hypoxia-induced neurodegeneration.
• Evaluation of the aqueous solubility and in vivo pharmacokinetic profile of SLOS-1811-06 tR1 following topical ocular administration in rabbits.

Main Results:

• The novel compound SLOS-1811-06 tR1 demonstrated potent neuroprotective effects at concentrations as low as 0.01 nM in vitro.
• SLOS-1811-06 tR1 exhibited high aqueous solubility (21.04 ± 0.08 mg/mL), facilitating eye drop formulation.
• A single topical dose of 0.5% SLOS-1811-06 tR1 in rabbits resulted in posterior retinal/choroidal concentrations of 4.4 ± 2.7 nM, exceeding the effective in vitro concentration.

Conclusions:

• SLOS-1811-06 tR1 is a potent non-covalent NRF2 activator with favorable physicochemical properties for topical ocular delivery.
• The compound demonstrated significant neuroprotection in a relevant disease model and achieved therapeutic concentrations in the retina after topical application.
• SLOS-1811-06 tR1 represents a promising drug candidate for the topical treatment of glaucoma and other oxidative stress-related ocular neurodegenerative diseases.