Woltersdorf O W, Schwam H, Bicking J B, Brown S L, deSolms S J, Fishman D R, Graham S L, Gautheron P D, Hoffman J M, Larson R D
Merck Sharp & Dohme Research Laboratory, West Point, Pennsylvania 19486.
J Med Chem. 1989 Nov;32(11):2486-92. doi: 10.1021/jm00131a011.
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.
制备了一系列6-羟基苯并噻唑-2-磺酰胺（4，L-643,799）的O-酰基衍生物，并测定了每个系列成员作为眼部碳酸酐酶局部活性抑制剂的潜在效用。体外研究表明，这些酯是眼部酯酶的底物，在角膜转运过程中会释放出4。最有趣的系列成员2-氨磺酰基-6-苯并噻唑基2,2-二甲基丙酸酯（22，L-645,151）作为4的前药形式，与母体酚4相比，经离体白化兔角膜给药时的递送效率提高了40倍。在兔身上的研究表明，22是一种有效的局部活性眼部降压碳酸酐酶抑制剂。
