Peptidomimetic prodrug

Mandal PK, Liao WSL, McMurray JS (2009) Synthesis of phosphatase-stable, cell-permeable peptidomimetic prodrugs that target the SH2 domain of StatS. Org Lett 11 3394—3397... 

The present chapter focuses on specific aspects of these challenges, namely peptide bond hydrolysis (chemical and enzymatic) and intramolecular reactions of cyclization-elimination (Fig. 6.4). This will be achieved by considering, in turn a) the enzymatic hydrolysis of prodrugs containing a peptide pro-moiety (Sect. 6.2), b) the chemical hydrolysis of peptides (Sect. 6.3), c) the enzymatic hydrolysis of peptides containing only common amino acids (Sect. 6.4), d) the hydrolysis of peptides containing nonproteinogenic amino acids (Sect. 6.5), and, finally, e) the hydrolysis of peptoids, pseudopeptides and peptidomimetics (Sect. 6.6). 

The derivatization of a basic function is exemplified by the amidine peptidomimetic of structure 8.156 (R = Rr = H), an inhibitor of the platelet membrane glycoprotein GPIIbIIIa [202], The compound is a zwitterion at physiological pH and showed limited oral bioavailability. A double prodrug... 

G. P. Camenisch, W. Wang, B. Wang, R. T. Borchardt, A Comparison of the Bioconversion Rates and the Caco-2 Cell Permeation Characteristics of Coumarin-Based Cyclic Prodrugs and Methylester-Based Linear Prodrugs of RGD Peptidomimetics , Pharm. Res. 1998, 15, 1174- 1181. 

Pauletti, G.M., S. Gangwar,T.J. Siahaan, A. Jeffrey, and R.T. Borchardt. 1997. Improvement of oral peptide bioavailability Peptidomimetics and prodrug strategies. Adv. Drug Deliv. Rev. 27 235-256. 

Fosamprenavir calcium has been approved for the treatment of HIV in adults when used in combination with other anti-HIV drugs. It is a prodrug that, on hydrolysis by serum phosphatases, gives rise to amprenavir, which is a peptidomimetic transition-state inhibitor that targets HIV-1 protease and reduces the viral replication and, thus, the infectiousness of HIV-1. It is commonly administered in combination with RT inhibitors to produce excellent efficacy in patients with AIDS. The drug is administered as two 700 mg tablets twice daily or, in combination with ritonavir, can be given as two 700 mg tables once daily or one 700 mg tablet twice daily. As a result, formaprenavir lowers the pill burden in patients with AIDS. 

Pauletti, G. M., Gangwar, S., Siahaan, T. J., Aube, J., Borchardt, R. (1997). Improvement of oral peptide bioavailability peptidomimetics and prodrug strategies. Advanced Drug Delivery Reviews, 27, 235-256. 

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