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MK-927: a topically active ocular hypotensive carbonic anhydrase inhibitor
M F Sugrue1, P Gautheron, J Grove
1Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania.
Journal of Ocular Pharmacology
|January 1, 1990
Summary
MK-927, a carbonic anhydrase inhibitor, effectively lowered intraocular pressure in hypertensive monkeys and rabbits. This topical ocular hypotensive agent demonstrated dose-dependent effects and is selected for glaucoma patient evaluation.
Area of Science:
- Ophthalmology
- Pharmacology
- Biochemistry
Background:
- Carbonic anhydrase inhibitors (CAIs) are utilized for managing intraocular pressure (IOP).
- MK-927 is a novel, water-soluble CAI with potent in vitro activity against human carbonic anhydrase II.
Purpose of the Study:
- To evaluate the ocular hypotensive efficacy of MK-927 in preclinical models.
- To assess the dose-dependency, duration, and ocular tissue distribution of MK-927.
Main Methods:
- Topical ocular instillation of various MK-927 concentrations in cynomolgus monkeys (hypertensive and normotensive) and alpha-chymotrypsinized rabbits.
- Measurement of intraocular pressure (IOP) changes.
- In vitro assessment of ocular pigment binding and ex vivo ocular tissue concentration analysis in pigmented and albino rabbits.
Main Results:
- MK-927 significantly reduced IOP in a dose-dependent manner in both hypertensive monkeys and rabbits.
- Peak IOP reduction in monkeys was observed 2-4 hours post-instillation, with effects waning by 6 hours.
- Ocular pigment binding was modest; higher MK-927 concentrations were found in ocular tissues of pigmented rabbits, correlating with a more pronounced and sustained hypotensive effect.
Conclusions:
- Topical MK-927 demonstrates significant ocular hypotensive activity in relevant animal models.
- The drug's efficacy is influenced by ocular pigmentation, suggesting potential variations in patient response.
- MK-927 is a promising candidate for topical glaucoma therapy and warrants clinical evaluation in patients.