Prodrug forms for the sulfonamide group. II. Water-soluble amino acid derivatives of N-methylsulfonamides as possible prodrugs

Abstract

Various N-acyl derivatives (acetyl, benzoyl, N, N-diethylaminoacetyl and morpholinoacetyl) of the model sulfonamide N-methyl- p-toluenesulfonamide were synthesized and evaluated as potential prodrug forms for the sulfonamide group occurring in e.g. carbonic] anhydrase inhibitors. The kinetics of hydrolysis of the derivatives were determined at 37°C in the pH range 0–12 and in the presence of human plasma. Maximal stability was achieved at pH around 4. The N-acyl compounds were readily hydrolyzed enzymatically to yield the parent sulfonamide in quantitative amounts. The derivatives with an ionizable amino function in the acyl moiety possess a high water-solubility as well as adequate lipophilicity at physiological pH. Since various N-methylsulfonamides are known to undergo demethylation in vivo a promising prodrug approach for a primary sulfonamide may be N-acylation of the corresponding N-methylsulfonamide.