Prodrugs amino acid

Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include L-3,4-dihydroxyphenylalanine (L-dopa) to the brain [56], dipivaloyl derivative of epinephrine to the eye [57], /-glutamyl-L-dopa to the kidney [58], fi-n-glucoside dexamethasone and prednisolone derivatives to the colon [59], thiamine-tetrahydrofuryldisulfide to red blood cells, and various amino acid derivatives of antitumor agents such as daunorubicin [61,62], acivicin [63], doxorubicin [63], and phenylenediamine [63] to tumor cells. 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

M Asgharnejad. Investigation into intestinal transport and absorption of an amino acid, amino acid analougue and its peptideomimetic prodrug. PhD dissertation, Chapter IV. pp 109-127, The University of Michigan, 1992. 

Han, H.-K., D.-M. Oh, and G. L. Amidon. Cellular uptake mechanism of amino acid ester prodrugs in Caco-2/hPEPTl cells overexpressing a human peptide transporter. Pharm. 

Carrier-mediated prodrug absorption has especially focused upon the use of PepTl, and a variety of strategies using stabilized dipeptides and amino acid-based prodrugs with affinity to hPepTl appear promising. In retrospect, it has been shown that the commercially available prodrugs valaciclovir and valganciclovir are both absorbed via hPepTl, which provides evidence for the value of the carrier-mediated concept. 

Yang C, Gao H, Mitra AK (2001) Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir. J Pharm Sci. 90 617-624. 

T. Hatanaka, M. Haramura, Y. J. Fei, S. Miyauchi, C. C. Bridges, P. S. Ganapathy, S. B. Smith, V. Ganapathy, and M. E. Ganapathy. Transport of amino acid-based prodrugs by the Na" - and Cl -coupled amino acid transporter ATB° + and expression of the transporter in tissues amenable for drug delivery. J Pharmacol Exp Ther 308 1138-1147(2004)... 

X. Song, P. L. Lorenzi, C. P. Landowski, B. S. Vig, J. M. Hilfinger, and G. L. Amidon. Amino acid ester prodrugs of the anticancer agent gemcitabine synthesis, bioconversion, metabolic bioevasion, and hPEPTl-mediated transport. Mol Pharm 2 157-167 (2005). 

Based on the idea that pyrrolidines can be metabolized selectively to y-aminobutyric acid derivatives, Wall and Baker [189] developed a retro-metabolic approach with 3-(4-chlorophenyl)pyrrolidine (5.92, Fig. 5.25) as a prodrug for the GABA-ergic agent baclofen (5.93, Fig. 5.25). In vitro studies showed that metabolism of 5.92 yields a pair of isomeric lactam metabolites (5.94, 5.96) and a pair of isomeric amino acid metabolites (5.93, 5.95). The formation of the metabolites resulting from the oxidation... 

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). 

Preliminary information useful in prodrug design has been obtained with amino acids attached to model aromatic amines. Thus, N-(naphthalen-2-yl) amides of amino acids (6.1, R=side chain of amino acid, R =H) proved to be of interest as test compounds to monitor peptidase activity such as ami-nopeptidase M (membrane alanyl aminopeptidase, microsomal aminopepti-dase, EC 3.4.11.2) [16][17], In the presence of purified rabbit kidney aminopeptidase M or human cerebrospinal fluid (CSF) aminopeptidase activity, the rate of hydrolysis decreased in the order Ala-> Leu->Arg->Glu-2-naphthyl-amide. Ala-2-naphthylamide, in particular, proved to be a good test compound, as its rate of hydrolysis was influenced by experimental conditions (preparation, inhibitors, etc.), as was the hydrolysis of a number of low-molecular-weight opioid peptides and circulating vasoactive peptides. 

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