title: MK-927: a topically active ocular hypotensive carbonic anhydrase inhibitor.
abstract: 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.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania.
authors.forename: M F
authors.initials: MF
authors.lastname: Sugrue
authors.forename: P
authors.initials: P
authors.lastname: Gautheron
authors.forename: J
authors.initials: J
authors.lastname: Grove
authors.forename: P
authors.initials: P
authors.lastname: Mallorga
authors.forename: M P
authors.initials: MP
authors.lastname: Viader
authors.forename: H
authors.initials: H
authors.lastname: Schwam
authors.forename: J J
authors.initials: JJ
authors.lastname: Baldwin
authors.forename: M E
authors.initials: ME
authors.lastname: Christy
authors.forename: G S
authors.initials: GS
authors.lastname: Ponticello
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D002918:Chymotrypsin / Q000494:pharmacology; D002924:Ciliary Body / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects; D007498:Iris / Q000378:metabolism; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D009798:Ocular Hypertension / Q000188:drug therapy; D011817:Rabbits; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D002918:Chymotrypsin; C057921:sezolamide