Program

PO1-13-24

INTRAOCULAR PRESSURE LOWERING EFFECT OF IMIDAZO[1, 2-a] BENZIMIDAZOLE AND PYRIMIDO[1, 2-a]BENZIMIDAZOLE COMPOUNDS IN OCULAR NORMOTENSIVE AND HYPERTENSIVE RATS

[Speaker] Igor Iezhitsa:1,2
[Co-author] Adrian J Marcus:1, Renu Agarwal:1, Pavel Vassiliev:2, Alexander Spasov:2, Olga Zhukovskaya:3, Vera Anisimova:3, Nafeeza Mohd Ismail:1
1:Universiti Teknologi MARA, Faculty of Medicine, Associate Professor of Pharmacology, Malaysia, 2:Volgograd State Medical University, Research Institute of Pharmacology, Russia, 3:Southern Federal University, Research Institute of Physical and Organic Chemistry, Russia

Introduction. Primary open-angle glaucoma is the second leading cause of blindness in the world and ocular hypertension is believed to play an important role in its pathophysiology. Hence, reduction in intraocular pressure (IOP) remains the primary therapeutic target. Objectives. In an effort to find new ocular hypotensive drug, a total of 28 imidazo[1,2-a]- and pyrimido[1,2-a]benzimidazole compounds were screened for their IOP lowering activity in ocular normotensive and hypertensive rats. Methodology. IOP lowering activity was determined by assessing IOP maximum decrease from baseline and control, duration of activities and area under the curve (AUC). During initial screening of 28 compounds, four compounds RU 551, RU 555, RU 839, and RU 615 showed significant IOP lowering activities in ocular normotensive rats. On the next step, IOP lowering effect of unilateral single drop application of all four compounds was tested at 0.1% concentration and then lead compound was similarly tested for dose-related relationship at 3 different concentrations (0.1%, 0.2% and 0.4%) in ocular hypertensive rats. This was followed by evaluation of ocular hypotensive effect of bilateral multiple drop administration of minimally effective concentration of lead compound for 3-weeks in ocular hypertensive rats. Results. It was shown that single drop of RU-615 showed significantly greater IOP lowering effect in ocular hypertensive rats when compared to RU-551, RU-555, and RU-839. There were no significant differences among all tested concentrations, hence the lowest concentration was selected for chronic treatment. Chronic topical application of RU615 caused significant IOP reduction from baseline though out the 3 weeks treatment period with max IOP reduction of 30.31 % at day 15 and remains constant on days 18 and 21. In conclusion, RU-615, a novel N9-imidazobenzimidazole derivatives, exhibits significant IOP lowering effect in both normotensive and ocular hypertensive rats.
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