Enkephalins prodrugs

Figure 25. The adamantane-conjugated [D-Ala2]Leu-enkephalin prodrugs. Taken from Ref. [144] with permission.

Rasmussen, G. J., Bundgaard, H., Prodrugs of peptides 15. 4-Imida-zolidinone prodrug derivatives of enkephalines to prevent aminopep-tidase-catalyzed metabolism in plasma and absorptive mucosae, Int. J. 

G. J. Rasmussen, H. Bundgaard, Prodrugs of Peptides. 15. 4-hnidazolidinone Prodrug Derivatives of Enkephalins to Prevent Aminopeptidase-Catalyzed Metabohsm in Plasma and Absorptive Mucosa , Int. J. Pharm. 1991, 76, 113- 122. 

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],... 

Figure 13.12. Schematic representation of enzyme-mediated targeting of enkephalin using a prodrug strategy.

One of the simplest methods of improving the uptake of a dmg to the brain involves the conversion of the drag to a more lipophilic prodrug (see Section 1.3.4.1). Using this approach, moderate increases in transport across the BBB have been achieved for enkephalin analogs and TRH. 

Combined inhibitors of enkephalin-degrading enzymes Prodrugs... 

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