Discovery of Potent and Selective Urea-Based ROCK Inhibitors and Their Effects on Intraocular Pressure in Rats

Area of Science:

• Medicinal Chemistry
• Ophthalmology
• Pharmacology

Background:

• Glaucoma is a leading cause of irreversible blindness worldwide.
• Elevated intraocular pressure is a primary risk factor for glaucoma progression.
• Rho kinase (ROCK) pathway is implicated in regulating intraocular pressure.

Purpose of the Study:

• To design and synthesize novel urea-based Rho kinase (ROCK) inhibitors.
• To evaluate the pharmacological properties of these inhibitors for antiglaucoma potential.
• To assess their suitability for topical ophthalmic drug delivery.

Main Methods:

• Synthesis of a series of urea-based compounds.
• In vitro enzyme inhibition assays to determine potency and selectivity.
• Cellular assays to assess compound activity.
• Physicochemical property evaluation (solubility, LogP).
• Ex vivo porcine corneal penetration studies.
• In vitro drug metabolism and pharmacokinetic (DMPK) profiling.

Main Results:

• Discovered urea-based compounds demonstrated excellent enzyme and cellular potency against ROCK.
• Compounds exhibited high kinase selectivity, minimizing off-target effects.
• Achieved high aqueous solubility, crucial for topical formulations.
• Showed good penetration through porcine cornea.
• Exhibited appropriate drug metabolism and pharmacokinetic (DMPK) profiles for ophthalmic application.

Conclusions:

• The designed urea-based ROCK inhibitors possess promising pharmacological profiles.
• These compounds represent potential therapeutic candidates for topical antiglaucoma treatment.
• Favorable physicochemical and DMPK properties support further development for ophthalmic delivery.