N-(Acyloxyalkoxycarbonyl) derivatives as potential prodrugs of amines. II. esterase-catalysed release of parent amines from model prodrugs

Abstract

N-(Acetoxyethoxycarbonyl) derivatives of primary amines released a major fraction of the parent amine in the desired free form in plasma but a significant fraction of the undesired N-acetylated parent amine was also produced. The fraction of the parent amines released from the carbamate derivatives of the primary amines was greater in human plasma than in pH 7.4 buffer. In human plasma, the N-(acetoxyethoxycarbonyl) derivative of a secondary amine released the parent amine in a quantitative manner at a rate higher than that observed in pH 7.4 buffer. Experimental results suggested that the observed catalysis of the release of the parent amines from N-(acetoxyethoxycarbonyl) derivatives of primary and secondary amines was due to participation by plasma esterases. The data suggested that N-(acetoxyethoxycarbonyl) derivatives are well suited for use as prodrugs of secondary amines. Their utility as prodrugs of primary amines is more problematic and cannot be predicted prior to in-vivo studies for the individual compound.