Specific analogs of ethoxzolamide will be synthesized and evaluated. These analogs are designed for the purpose of promoting penetration and distribution into the eye from a topically applied dose. From previous results and based upon a mathematical model, four additional 6-substituted analogs of ethoxzolamide will be synthesized: methylamino, acetamino, methoxymethyl and carboxyethyl. These are classical inhibitors designed for optimal corneal transport. In addition to optimal transport, a 6-amino analog of ethoxzolamide has been found to be five-fold more potent than ethxzolamide. Lipophilic substitution will optimize its transport. Furthermore, N-alkyl and/or N-hydroxyl sulfonamides have been identified which are potent """"""""nonclassical"""""""" inhibitors of carbonic anhydrase. Their potency will be optimized by systematically synthesizing various N-substituted sulfonamides. These results will provide information for the design, synthesis and evaluation of 6-substituted and N-substituted ethoxzolamide analogs. These analogs will represent both optimal corneal transport and optimal potency. The following information will be determined for most synthesized analogs; physical-chemical properties (partition coefficients, CAI, pKa and excised corneal permeability coefficients), pharmacological properties (duration of intraocular pressure, dose-response, and efficacy of repeated doses), pharmacokinetic properties (iris/ciliary body, aqueous humor, cornea and blood concentrations over time) and biochemical properties (type of carbonic anhydrase inhibition and Ki values). From this work a topical carbonic anhydrase inhibitor will be identified as a candidate for testing in glaucoma patients.
