Peptides double prodrugs

Cyclization-Activated Double Prodrugs of Amines and Peptides... 

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],... 

Fig. 8.24. Schematic representation of cyclic, double prodrugs of peptides and their mechanism of activation by enzymatic ester cleavage, followed by cyclization-elimination [168][169][238]...

Coumarinic acid is another phenylpropanoic acid pro-moiety used to prepare double prodrugs of amines (in analogy with the phenylpropanamides shown in Fig. 8.23), as well as cyclic prodrugs of a number of peptides (8.189) [242-246], These studies confirm the considerable potential of the cyclic prodrug strategy, such compounds being characterized by metabolic stability to peptidases and good cellular permeation. 

Fig. 33.23 Proposed conversion of esterase-sensitive and redox-sensitive double prodrugs of peptides. ...

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