N-Acyl derivatives as prodrug forms for amides: Chemical stability and enzymatic hydrolysis of various N-acyl and N-alkoxycarbonyl amide derivatives

Abstract

The hydrolysis kinetics and enzymatic cleavage of various N-acyl and N-alkoxycarbonyl derivatives of benzamide, N- methylbenzamide and salicylamide, used as models for the carboxamide group, were studied to assess their suitability as prodrugs for the amide group occurring in various drug substances and bioactive peptides. The pH-rate profiles for the hydrolysis of the derivatives were obtained at 37°C and the products of hydrolysis determined by HPLC analysis. NAcylated amides (diacylamines) were found to be relatively stable in aqueous solution but readily hydrolyzed enzymatically by human plasma. The amount of parent amide formed upon both chemical and enzymic hydrolysis was shown to depend on the nature of the N-acyl group. The N-acyloxycarbonyl derivatives ( N-acyl carbamates) degraded predominantly to the acid of the parent amide and are suggested to be less suitable than N-acyl derivatives as prodrug forms for the amide functionality.