Ocular Hypotensive Effects of the New Ethacrynic Acid Derivative SA9000

Abstract

Abstract: : Purpose: Ethacrynic acid (ECA) has potent ocular hypotensive effects. Nevertheless, because of potential ocular side effects such as corneal edema, there is a need for derivatives of ECA with greater ocular safety. Therefore, we synthesized several ECA derivatives and evaluated their pharmacological and hypotensive effects. Methods: We synthesized thirty–two ECA derivatives and initially evaluated them for potency in a cell–shape assay using human trabecular meshwork (TM) cells, and for cytotoxicity in a MTS assay using bovine TM cells. Ocular hypotensive effects were measured in ocular normotensive cats and monkeys and laser–induced glaucomatous monkeys. Because it is well known that ECA inhibits the Na⁺–K⁺–Cl^– cotransporter, the effect of these ECA derivatives on Na⁺–K⁺–Cl^– cotransporter was evaluated by measuring the rate of ⁸⁶Rb uptake in C6 astrocytoma cells. Changes in TM cell monolayer permeability were quantified using a fluorescence method to evaluate FITC–dextran diffusion through TM cell monolayers grown in transwell chambers. Results: We found that SA9000 demonstrated greater potency and a broader therapeutic index than ECA in our cell–shape and MTS assays. An intracameral injection of 0.1 mM SA9000 significantly reduced intraocular pressure (IOP) by 3.8 mmHg in four ocular normotensive cats. In four ocular normotensive monkeys, intracameral injection of 1 mM SA9000 significantly reduced IOP by 7.0 mmHg without corneal edema. Repeated topical administration of 0.3% SA9000 also reduced IOP by 7.3 mmHg in four laser–induced glaucomatous monkeys at day 6. SA9000 (10 µM) did not inhibit the Na⁺–K⁺–Cl^– cotransporter unlike ECA. TM cell monolayer permeability increased by 71 % in response to SA9000 treatment (10 µM). Conclusions: These findings indicate that SA9000 has the potential to be both effective and safe as an ocular hypotensive drug and may exert its effects by changing TM cell morphology.

Keywords: intraocular pressure • trabecular meshwork