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Discovery and Preclinical Development of Novel Intraocular Pressure-Lowering Rho Kinase Inhibitor: Corticosteroid
Jill Sturdivant1, Stuart S Williams1, Maria Ina1
1Research & Development, Aerie Pharmaceuticals, Inc., Durham, North Carolina, USA.
Summary
A novel class of ocular steroids, ROCK'Sters, were developed to reduce intraocular pressure (IOP) without compromising anti-inflammatory effects. Compound 1 demonstrated efficacy in preclinical models, offering a promising new topical ocular treatment.
Area of Science:
- Ophthalmology
- Pharmacology
- Drug Discovery
Background:
- Steroid-induced intraocular pressure (IOP) elevation is a common side effect of topical ocular corticosteroids.
- Developing ocular steroids that maintain anti-inflammatory activity while mitigating IOP elevation is crucial for patient care.
Purpose of the Study:
- To discover and characterize a new class of ocular steroids, termed ROCK'Sters, designed to reduce IOP.
- To evaluate the anti-inflammatory efficacy and safety profile of lead compound 1 in preclinical models.
Main Methods:
- Synthesized Rho kinase inhibitor (ROCKi) and corticosteroid codrugs (ROCK'Sters).
- Screened compounds in vitro for ROCKi and anti-inflammatory activity.
- Assessed lead compound 1 for IOP lowering in rabbits and anti-inflammatory effects in post-surgical and allergic eye disease models.
Main Results:
- Several ROCK'Sters showed potent ROCK inhibition and in vitro anti-inflammatory activity.
- Compound 1 demonstrated significant IOP lowering without hyperemia in rabbits.
- Compound 1 exhibited noninferior anti-inflammatory efficacy compared to marketed steroids in rabbit and mouse models.
Conclusions:
- ROCK'Ster compound 1 is a novel, topically administered ocular drug candidate.
- Compound 1 possesses both IOP-lowering capability and potent anti-inflammatory activity, comparable to existing treatments.
- This new class of ocular steroids holds potential for managing inflammatory eye conditions with reduced IOP-related side effects.
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