ON THE PHARMACOLOGY OF L-645,151 - A TOPICALLY EFFECTIVE OCULAR HYPOTENSIVE CARBONIC-ANHYDRASE INHIBITOR

Abstract

L-645,151 [(2-sulfamoyl-6-benzothiazolyl)-2,2-dimethylpropionate] is the O-pivaloyl ester of L-643,799 (6-hydroxybenzothiazole-2-sulfonamide), topically administered L-645,151 being a substrate for ocular esterases with the resultant liberation of the active moiety, L-643,799, during penetration of the ocular surface. The minimum concentrations of topically administered suspensions (1 drop of 50 .mu.l into both eyes) of L-645,151, L-643,799, dichlorphenamide and methazolamide significantly lowering the elevated intraocular pressure (IOP) of the .alpha.-chymotrypsinized rabbit eye were 0.25, 2, 10 and 5%, respectively. IOP was not significantly decreased by 10% suspensions of acetazolamide or ethoxzolamide. The IOP lowering action of L-645,151 was local as the unilateral instillation of L-645,151 (0.25%) into the contralateral eye was devoid of effect in .alpha.-chymotrypsinized rabbits. L-645,151 (2%) decreased aqueous humor inflow in both the conscious rabbit and the anesthetized dog. Outflow facility in the conscious rabbit was unaltered by a 10% suspension of L-645,151. Low peak levels (0.52 .mu.g/g) of L-643,799 were present in rabbit renal cortex after the instillation of L-645,151 (2%) into both eyes; this treatment did not induce diuresis in the conscious rabbit. The corresponding maximum concentration in the iris + ciliary body was 4.01 .mu.g/g. These preclinical studies reveal that L-645,151 is the most potent, topically effective ocular hypotensive carbonic anhydrase inhibitor described to date.