Topical L-662,583: A Potent Carbonic Anhydrase Inhibitor for Ocular Hypotension in Animal Models

L-662,583 demonstrated strong inhibitory effects on human red blood cell carbonic anhydrase II in laboratory tests, with an IC50 value of 0.7 nM, outperforming MK-927, acetazolamide, and methazolamide which had IC50 values of 13.0 nM, 10.8 nM, and 21.2 nM respectively. In an ex vivo study using albino rabbits, a 50 μl drop of a 0.1% L-662,583 solution applied for 1 hour resulted in a 63% inhibition of carbonic anhydrase activity in the iris and ciliary body, surpassing the 30% and 20% inhibitions caused by similar treatments with acetazolamide and methazolamide.

High-performance liquid chromatography was used to determine L-662,583 concentrations in the cornea, aqueous humor, and iris plus ciliary body of albino rabbits at specific times after applying a single drop of a 2% solution. Peak levels were observed at 0.5 hours for the cornea (47.4 μg/g), 2 hours for the aqueous humor (4.51 μg/ml), and 1 hour for the iris plus ciliary body (9.61 μg/g).

In rabbits with artificially elevated intraocular pressure caused by α-chymotrypsin injection, L-662,583 reduced pressure by 4.5 mmHg, 6.2 mmHg, and 9.8 mmHg following the application of 0.01%, 0.1%, and 0.5% solutions, respectively. These effects were observed from 1 to 5 hours post-application. The unilateral application of L-662,583 did not affect the untreated eye, indicating a localized effect. Normotensive rabbits were less responsive to the pressure-lowering effects of L-662,583, with a 2% solution reducing pressure by only 2.3 mmHg.

In cynomolgus monkeys with induced ocular hypertension, a single drop of 2% L-662,583 significantly reduced intraocular pressure by a maximum of 8.3 mmHg at 3 hours, a 23% reduction from the baseline. The normotensive eyes of the monkeys were more resistant to the hypotensive effects of L-662,583 compared to hypertensive eyes, with a 2% solution reducing pressure by 2.4 mmHg at 2 hours.

L-662,583, structurally distinct from MK-927, is a water-soluble carbonic anhydrase inhibitor that lowers intraocular pressure when applied topically, with its effects being localized within the eye, similar to MK-927.