Carbonic Anhydrase Inhibitor Prodrugs

Oral carbonic anhydrase inhibitors (CAIs) have already been in clinical use for 50 years in the treatment of increased IOP (Sugrue, 1989). The currently used oral CAIs include acetazolamide and methazolamide. However, patient compliance with systemic CAI medication is poor, due to side effects such as hypokalemia, fatigue, depression, gastrointestinal disturbances, and anorexia (Epstein and Grant, 1977; Lichter et al., 1978). Because the topical administration of CAIs was clinically ineffective, researchers started to explore other methods of drug delivery, including the prodrug approach (Sugrue et al., 1985; Grove et al., 1988; Woltersdorf et al., 1989) and cyclodextrin-technology (Javitt et al., 1994; Loftsson et al., 1994) to increase the topical activity of CAIs. The prodrug approaches, described below, were undertaken before the advent of topical dorzolamide solution and brinzolamide suspension in the 1990s (Sugrue, 2000). These compounds are CAI analogs, however, and not prodrugs.

Prodrugs of CAI derivatives have been designed either to increase low aqueous solubility or to increase lipophilicity as strategies to enhance corneal permeation. A series of O-acyl derivatives of 6-hydroxybenzothiazole-2-



Scheme 3.

Pilocarpine sulphonamide (L-643,799) were evaluated as topically active CAIs (Woltersdorf et al., 1989). L-643,799 (23) is an analog of ethoxzolamide (22), which has been used in oral CAI medication. Prodrugs were converted to active CAI (L-643,799) in cornea homogenate and improved the corneal permeation of L-643,799 in vitro. The pivaloyl ester of 6-hydroxybenzothiazole-2-sulphonamide (L-645,151) (24) was the most interesting prodrug of the series; it significantly lowered IOP in rabbits (Sugrue et al., 1985). However, clinical development of this prodrug was discontinued due to problems of sensitization (Grove et al., 1988). Schoenwald and Barfknecht (1991) have subsequently described water-soluble prodrugs of 2-benzothiazolesulphonamide, hydroxymethazolamide, and dichlorphen-amide.

Structures 22-24.

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