On the pharmacology of L-645,151: a topically effective ocular hypotensive carbonic anhydrase inhibitor

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 232; no. 2; p. 534
• Main Authors: Sugrue, M F, Gautheron, P, Schmitt, C, Viader, M P, Conquet, P, Smith, R L, Share, N N, Stone, C A
• Format: Journal Article
• Language: English
• Published: United States 01-02-1985
• Subjects: Administration, Topical; Animals; Benzothiazoles; Carbonic Anhydrase Inhibitors - administration & dosage; Carbonic Anhydrase Inhibitors - metabolism; Chymotrypsin - pharmacology; Diuretics; Dogs; Eye - metabolism; Female; Intraocular Pressure - drug effects; Male; Rabbits; Suspensions; Thiadiazoles - administration & dosage; Thiadiazoles - metabolism; Thiadiazoles - pharmacology; Thiazoles; Tissue Distribution
• ISSN: 0022-3565

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 microliters 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 microgram/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 micrograms/g. These preclinical studies reveal that L-645,151 is the most potent, topically effective ocular hypotensive carbonic anhydrase inhibitor described to date.