Prodrugs, peptide

Yee, S. and G. L. Amidon. Oral absorption of angiotensin-converting enzyme inhibitors and peptide prodrugs. In Peptide-based Drug Design. G. L. Amidon (ed), American Chemistry Society, Washington DC 1995, 137-147. 

Peptide-Prodmgs and the Cyclic Peptide-Prodrug Concept I 535... 

Golomb, G., A peptide prodrug approach for improving bisphos-phonate oral absorption, J. Med. 

Bitha, P., Lin, Y. I., Testa, T., In vivo activities of peptide prodrugs of novel aminomethyl tetrahydrofuranyl-1 beta-methylcarbapenems, Antimicrob. 

A series of peptide prodrugs ofh-a-methyldopa were prepared and shown to exhibit high affinity for the peptide carrier system [32], In an in situ intestinal perfusion model, the prodrugs Phe-L-a-methyldopa (6.10) and l-a-methyldopa-Phe (6.11) showed permeabilities that were 10- and 20-times higher, respectively, than that of L-a-methyldopa. The other derivatives examined (Gly- and Pro-L-a-methyldopa, L-a-methyldopa-Pro) also had better permeabilities. These and other results indicate that the peptide transport system has a relatively low substrate specificity and can indeed be targeted by peptide prodrugs to improve absorption [33],... 

Increased permeability is just one prerequisite in the development of useful peptide prodrugs. Another condition is that efficient bioactivation must follow absorption. Mucosal cell enzymes able to hydrolyze peptides include exopeptidases such as aminopeptidases and carboxypeptidases, endopepti-dases, and dipeptidases such as cytosolic nonspecific dipeptidase (EC 3.4.13.18), Pro-X dipeptidase (prolinase, EC 3.4.13.4), and X-Pro dipeptidase (prolidase, EC 3.4.13.9). For example, L-a-methyldopa-Pro was shown to be a good substrate for both the peptide transporter and prolidase. This dual affinity is not shared by all dipeptide derivatives, and, indeed, dipeptides that lack an N-terminal a-amino group are substrates for the peptide transporter but not for prolidase [29] [33] [34],... 

The oral absorption of an entirely different class of drugs, namely bisphosphonates, has also been improved by a peptide prodrug strategy [36]. The drugs pamidronate (6.13, n=2) and alendronate (6.13, n=3) were deriv-atized with the Pro-Phe-dipeptidyl unit to yield the prodrugs Pro-Phe-pamidronate (6.14, n=2) and Pro-Phe-alendronate (6.14, n=3), the ob-... 

Fig. 6.9. Rationale for the design of peptidic prodrugs (6.15) of 5-fluorouracil (6.17) targeting microbial peptides permeases and peptidases [37]...

Fig. 6.11. Peptide prodrugs (6.20, 6.21, and 6.22) for the intestine-selective delivery of 5-aminosalicylic acid (6.23). The prodrugs undergo selective activation by intestinal brush border enzymes, namely aminopeptidase A and/or carboxypeptidases [39].

A. Ezra, A. Hoffman, E. Breuer, I. S. Alferiev, J. Monkkonen, N. El Hanany-Rozen, G. Weiss, D. Stepensky, I. Gati, H. Cohen, S. Tormalehto, G. L. Amidon, G. Golomb, A Peptide Prodrug Approach for Improving Bisphosphonate Oral Absorption , J. Med. Chem. 2000, 43, 3641-3652. 

Enzyme-Mediated, Tissue-Selective Targeting of Peptide Prodrugs... 

Denmeade SR, Nagy A, Gao J, Lilja H, Schally AV, Isaacs JT. Enzymatic activation of a doxorubicin-peptide prodrug by prostate-specific antigen. Cancer Res 1998 58 2537-2540. 

Bisphosphonates pamidronate and alendronate (the most active bisphos-phonates approved for clinical use) were converted into the peptidyl prodrugs prolyl-phenylalanylpamidronate [Pro-Phe-pamidonate (420)] and prolyl-phenylalanyl-alendronate [Pro-Phe-alendronate (421)]. It was shown that the bioavailability of bisphosphonates can be enhanced by using the peptide prodrug approach. The increased oral absorption of the prodrugs was reduced by an active carrier-mediated transport. ... 

Ezra, A. Hoffman, A. Breuer, E. Alferiev, I.S. Monkko-nen, J. ElHanany-Rozen, N. Weiss, G. Stepensky, D. Gati, I. Cohen, H. Tormalehto, S. Amidon, G.L. Golomb, G. A peptide prodrug approach for improving bisphosphonate oral absorption. J. Med. Chem. 2000, 43, 3641-3652. 

Prodrug strategies have been very successful with small molecules however, the use of prodrugs for peptides has been less frequent.44 The cyclic peptide prodrug approach has been shown to improve membrane permeation. In this method, the... 

Still another intramolecular cyclization system is the coumarin-based prodrug system 134 that can be used for bioreversible derivatization of amine and alcohol drugs and the preparation of cyclic peptide prodrugs (Scheme 23).76,77 This system takes advantage of the known facile lactonization of coumarinic acid and its... 

FIGURE 36.9 Imine, enamine and peptide prodrugs derived from amino functions. 

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