Discovery of novel ROCK inhibitors RX-021 and RX-044 with intraocular pressure-lowering effect for glaucoma treatment

Area of Science:

• Pharmacology
• Ophthalmology
• Drug Discovery

Background:

• Glaucoma is a leading cause of irreversible blindness.
• Rho-kinase (ROCK) inhibitors represent a promising therapeutic target for lowering intraocular pressure (IOP).
• Optimization of existing lead compounds is crucial for developing novel therapeutics.

Purpose of the Study:

• To identify and characterize novel ROCK inhibitors with enhanced efficacy for glaucoma treatment.
• To evaluate the intraocular pressure-lowering and retinal neuroprotective effects of new compounds.
• To assess the safety and tolerability profile of the novel inhibitors.

Main Methods:

• Systematic optimization of a lead compound (D25) to identify novel ROCK inhibitors (RX-021 and RX-044).
• In vitro biochemical assays to determine ROCK1/2 inhibition and kinase selectivity.
• In vivo studies using a mouse ocular hypertension model to assess IOP reduction and retinal protection.
• Assessment of cytotoxicity in human trabecular meshwork (HTM) cells and ocular irritation in vivo.

Main Results:

• RX-044 demonstrated potent ROCK1/2 inhibition (IC50 values in nanomolar range) with favorable kinase selectivity and no cytotoxicity.
• RX-021 showed superior IOP reduction in a mouse model compared to (S)-Netarsudil, with sustained 24-hour efficacy.
• Both RX-021 and RX-044 provided significant retinal neuroprotection, preserving retinal ganglion cells and improving retinal function.
• Reversible ocular effects were observed, with initial irritation subsiding upon extended dosing.

Conclusions:

• RX-021 and RX-044 are novel, potent ROCK inhibitors with significant potential for glaucoma therapy.
• These compounds offer enhanced IOP-lowering efficacy and robust retinal neuroprotection.
• The findings support further development of RX-021 and RX-044 as therapeutic agents for glaucoma.