Double prodrug concept

The concept, also called distal hydrolysis or the double prodrug concept, is illustrated by the use of 2-acyloxymethylbenzoic acids as amine protective functions, providing amides with the lability of esters (Figure 36.18a) and by the use of substituted vinyl esters [= (2-oxo-l,3-dioxol-yl)methyl esters] as lipophilic cascade carriers for carboxylic acid-containing drugs such as ampicillin or a-methyldopa or various cephalosporins (Figure 36.18b). 

The 3-(2-hydroxy-4,6-dimethylphenyl)-3-methylbutanoic acid shown in Fig. 8.23, as well as another phenylpropanoic derivative presented below, have been used as pro-moieties to prepare a number of prodrugs of therapeutic peptides [169] [238], Of interest here is that the pro-moiety is linked to the peptide by both amide and ester bonds to form a cyclic, double prodrug, the two-step activation of which is schematized in Fig. 8.24. Briefly, enzymatic hydrolysis of the ester bond unmasks a nucleophile (in this case, a phenol) that carries out an intramolecular attack on the amide bond, resulting in cy-clization of the pro-moiety and elimination of the peptide. [Leu5]enkephalin was one of the therapeutic peptides used to validate the concept, as illustrated in Fig. 8.25 [241],... 

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