The Effect of the H-1152P, a Potent Rho-Associated Coiled Coil-Formed Protein Kinase Inhibitor, in Rabbit Normal and Ocular Hypertensive Eyes

Abstract

Purpose: We wanted to determine the intraocular pressure (IOP)-lowering effect of H-1152P by utilizing a rabbit ocular hypertension-glaucoma model and normal eyes. H-1152P is a potent, Rho-associated, coiled, coil-forming protein kinase (ROCK) inhibitor. Methods: IOPs were monitored by a pneumatonometer in New Zealand White rabbits that were given topically administered H-1152P or vehicle alone. Animals were divided into four groups followed by topical administration of 0.1, 1.0, 10, and 28 mM H-1152P. To study the IOP-lowering effects on an elevated IOP model, a rabbit ocular hypertension model was created by water loading. All studies were carried out by monitoring of IOPs on H-1152P-administered right eyes and phosphate-buffered saline (PBS)-administered left eyes. Results: In normotensive IOP rabbits, topical administration of H-1152P significantly decreased IOPs by 46.1 ± 5.0% at 1% (28 mM) solution. This effect was dose dependent, as the maximum reduction of IOPs were observed between 60 and 90 min after topical administration (3.6 ± 0.9 mmHg, 5.4 ± 0.7 mmHg, 6.8 ± 0.7 mmHg, and 7.2 ± 1.9 mmHg at 0.1, 1.0, 10, and 28 mM H-1152P). In addition, in the rabbit ocular hypertension model, the topical administration of H-1152P (28 mM) significantly lowered IOPs starting at 30 minutes and lasting up to 300 minutes after water loading. The maximum IOP reduction, however, was observed at 90 minutes after water loading (10.6 ± 2.3 mmHg). No serious side effects were observedin ocular tissues except for some conjunctival congestion that shortly disappeared within 3 hours.Conclusion: Topical administration of H-1152P potently decreased rabbit normotensive IOPs in a dose-dependent manner, and the duration of the IOP lowering was also elongated in a dose-dependent manner. In addition, H-1152P has a potent IOP-lowering effect on an ocular hypertension model. These result suggested that H-1152P could be a candidate for the next generation of glaucoma therapy.