Topically active carbonic anhydrase inhibitors. 1. O-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamide.
A series of O-acyl derivatives of 6-hydroxybenzothiazole-2-sulfonamide (4, L-643,799) was prepared and the potential utility of each series member as a topically active inhibitor of ocular carbonic anhydrase was determined. In vitro studies showed these esters to be substrates for ocular esterases which liberate 4 during corneal translocation. The most interesting series member, 2-sulfamoyl-6-benzothiazolyl 2,2-dimethylpropionate (22, L-645,151), acting as a prodrug form of 4, was found to enhance delivery through the isolated albino rabbit cornea by 40-fold when compared to the parent phenol 4. Studies in rabbits revealed that 22 is a potent topically active ocular hypotensive carbonic anhydrase inhibitor.
Woltersdorf
O W
OW
Merck Sharp & Dohme Research Laboratory, West Point, Pennsylvania 19486.
Schwam
H
H
Bicking
J B
JB
Brown
S L
SL
deSolms
S J
SJ
Fishman
D R
DR
Graham
S L
SL
Gautheron
P D
PD
Hoffman
J M
JM
Larson
R D
RD
D000818:Animals; D052160:Benzothiazoles; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis; D055598:Chemical Phenomena; D002621:Chemistry; D003315:Cornea / Q000201:enzymology; D005016:Ethoxzolamide / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000031:analogs & derivatives; D006168:Guinea Pigs; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D009883:Ophthalmic Solutions; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D011817:Rabbits; D013844:Thiazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*
D052160:Benzothiazoles; D002257:Carbonic Anhydrase Inhibitors; D009883:Ophthalmic Solutions; D011355:Prodrugs; D013844:Thiazoles; C059454:6-hydroxybenzothiazide-2-sulfonamide; C044455:L 645151; D005016:Ethoxzolamide