ABSTRACT
This chapter focuses on modification approaches that have been adopted to generate prodrugs primarily for the purpose of improved solubility in water. It will be discovered that dramatic changes in the physicochemical properties can be observed upon minor chemical modifications. Successful prodrug prepared by this method is the hydrochloride salt of the N-(N',N'-dimethylglycyloxymethyl) derivative of chlorzoxazone that improved the solubility of the parent drug 1000-fold. Amino acid esters have been recommended as potentially useful progroups in that they provide the carboxylic acid group for reaction with an alcohol or phenol to form an ester prodrug, an ionizable amine as a side group, and the potential for another ionizable side group in certain amino acids. Most prodrugs are biologically inactive, and therefore, an important feature in the design of a prodrug is the sensitivity of the modification to cleavage through chemical or enzymatic means to release the promoiety and return the pharmacologically active agent.
