alpha-chymotrypsin and sezolamide

L-671,152 is a water-soluble, carbonic anhydrase inhibitor structurally similar to MK-927, a carbonic anhydrase inhibitor that, on topical administration, lowers the intraocular pressure (IOP) of experimental animals and humans. L-671,152 was more potent than MK-927 at inhibiting purified, human erythrocyte carbonic anhydrase II in vitro, as reflected in their respective IC50 values of 0.16 nM and 1.19 nM. Both compounds were compared for topical, ocular hypotensive activity in pigmented rabbits and cynomolgus monkeys. Ocular hypertension was induced in the latter by argon laser photocoagulation of the trabecular meshwork. A 2% solution of L-671,152 was more potent than 2% MK-927 in lowering the IOP of ocular hypertensive monkeys, the maximum reductions being 13.8 mm Hg (37%) and 9.6 mm Hg (27%) at 5 hr and 4 hr, respectively. Moreover, the duration of action of L-671,152 was superior to that of MK-927. The ocular hypotensive effect of L-671,152 was greater than that of MK-927 over a range of concentrations (0.5%-2%) in pigmented rabbits whose IOP was inherently elevated. The peak declines in the IOP of these rabbits after the instillation of 2% solutions of L-671,152 and MK-927 were 6.1 mm Hg and 4.8 mm Hg, respectively. L-671,152 was very effective in lowering the elevated IOP of alpha-chymotrypsinized rabbits and the unilateral instillation of 0.5% L-671,152 into the contralateral eye failed to decrease the elevated IOP of the alpha-chymotrypsinized eye. This finding indicates that the site of action of topically applied L-671,152 is local. The enhancement in the potency of L-671,152 over MK-927 is attributed to a greater inhibition of carbonic anhydrase activity.

Topics: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Chymotrypsin; Ciliary Body; Erythrocytes; Female; In Vitro Techniques; Iris; Light Coagulation; Macaca fascicularis; Male; Ocular Hypertension; Ocular Hypotension; Rabbits; Sulfonamides; Thiophenes; Trabeculectomy

MK-927 (dl-5,6-dihydro-4-(2-methylpropylamino)-4H-thieno(2,3b)thiopyra n-2-sulfonamide-7,7-dioxide hydrochloride) is a water soluble, carbonic anhydrase inhibitor (CAI) possessing a Ki of 12.0 nM against purified human carbonic anhydrase II in vitro. The acute instillation of one drop (50 microliters) of 0.5%, 1% and 2% solutions of MK-927 maximally decreased the intraocular pressure (IOP) of ocular hypertensive, cynomolgus monkeys by 4.7, 5.9 and 9.6 mm Hg, respectively. The decline of 9.6 mm Hg represented a reduction of 27% from the corresponding vehicle-treated value of 35.3 mm Hg. Peak reductions in IOP were present at 2 to 4 hr after the instillation of the three doses and the ocular hypotensive effect was waning at 6 hr. The IOP of normotensive, monkey eyes was significantly lowered by 1% and 2% solutions of MK-927 with the effect being more transient in these eyes than in hypertensive eyes. The elevated IOP of alpha-chymotrypsinized rabbits was dose-dependently decreased by 0.01%, 0.1% and 0.5% solutions of MK-927. MK-927 modestly bound to rabbit ocular pigment in vitro and the concentrations of MK-927 in the iris + ciliary body of pigmented rabbits were higher than those in the same tissue of albino rabbits after dosing with 0.5% MK-927. The ocular hypotensive effect of 2% MK-927 was greater in magnitude and longer in duration in normal pigmented than in albino rabbits. The IOP lowering action of MK-927 was local as evidenced by results of ocular distribution studies and the observation that the unilateral instillation of 0.5% MK-927 into the contralateral eye was devoid of effect on the untreated, hypertensive eye of alpha-chymotrypsinized rabbits. MK-927 has been selected for topical evaluation in glaucoma patients.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Chymotrypsin; Ciliary Body; Dose-Response Relationship, Drug; Female; Intraocular Pressure; Iris; Kinetics; Macaca fascicularis; Male; Ocular Hypertension; Rabbits; Sulfonamides; Thiophenes