And prodrug design

The impact of the above in terms of drug discovery and development suggests the seeming wide possibilities for substrate mimicry and prodrug design. Even though most dipeptides and tripeptides studied so far are substrates for PEPT1, a number of examples exist where affinity and translocation are absent, for example, observed for Lys-Lys, Trp-Trp, Arg-Arg, and Arg-Lys. 

Vinsova, J. and E. Vavrikova. 2008. Recent advances in drugs and prodrugs design of chitosan. Current Pharmaceutical Design 14 (13) 1311-1326. 

Although N-methyl-N-nitrosourea can induce cancer in human beings, its derivatives were found to be potent antitumor agents. l,3-Bis(2-chloroethyl)-l-nitrosourea (BCNU), l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) and l-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl-l-nitrosourea (PCNU) l-(2-Choroethyl)-3-(4-methylcyclo-hexyl)-l-nitrosourea and l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea showed antitumor activity by alkylating with DNA [82-84]. N-Nitrosourea-based prodrugs designed to become activated by tumor-associated proteases were found to provide enhanced... 

Prodrugs will receive much attention in this book (Chapt. 4, 6, 8, 9, and 11). It is, therefore, appropriate in this introductory chapter to clarify some definitions and review various aspects of prodrug design and research [11- 22],... 

Prodrug design aims to overcome a number of barriers to a drug s usefulness (Table 1.1). Based on these and other considerations, the major objectives of prodrug design can be listed as also shown in Table 1.1. 

The successes of prodrug design are many, and a large variety of such compounds have proven their therapeutic value. When discussing this multidisciplinary field of medicinal chemistry, several complementary viewpoints can be adopted, as listed in Table 1.2. 

Careful prodrug design is required to minimize the number of proposed candidates and maximize the explored space of physicochemical and pharmacokinetic properties. The ability to predict target properties (e.g., solubility, extent of absorption, and rate of activation) is a major need in rational prodrug design, but global quantitative models simply do not exist, despite... 

Table 1.3. Specific Difficulties in Prodrug Design and Development (modified from [22])a)...

B. Testa, J. M. Mayer, Concepts in Prodrug Design to Overcome Pharmacokinetic Problems , in Pharmacokinetic Optimization in Drug Research Biological, Physicochemical, and Computational Strategies , Eds. B. Testa, H. van de Waterbeemd, G. Folk-ers, R. Guy, Verlag Helvetica Chimica Acta, Zurich, 2001, p. 85-95. 

The next example is 1,3-dibenzoylurea (4.222), a diacetylated linear urea. The hydrolysis kinetics and enzymatic cleavage of 1,3-dibenzoylurea together with various other /V-acylbenzamides were studied to assess the suitability of these compounds as prodrugs for the amido group [113]. At pH 7.4 and 37°, 1,3-dibenzoylurea was hydrolyzed quantitatively to benzoic acid and N-benzoylurea (4.223) with a tm value of 39 h. Since the hydrolysis of 1,3-di-benzoylurea was not catalyzed by human plasma, it was concluded that the acyclic diureide structure is not appropriate in prodrug design. 

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. 

In summary, the various examples presented in this section illustrate the diversity of molecular factors that influence the many physicochemical and biochemical properties of significance in prodrug design. Many items of information are reported in this section, but the partial and fragmentary character hinders comprehensive understanding. Whether and how much such information can be rationalized is discussed in the next section. 

Ibuprofen (8.28) and naproxen (8.26) were derivatized with the same l-[(ethoxycarbonyl)oxy] ethyl pro-moiety to yield two prodrugs designated as... 

An esterifying substituent of value in prodrug design is the (2-oxo-l,3-dioxol-4-yl)methyl group (8.62 in Fig. 8.4). The interest in this moiety was first documented with prodrugs of antibiotics, as discussed below. To the best of our knowledge, no detailed or systematic studies on the mechanism of activation of (oxodioxolyl)methyl derivatives have been published. The available evidence supports a clean reaction of base-catalyzed hydrolysis as shown in Fig. 8.4, although the actual mechanism may be more complex and/or condition-dependent [74][75]. Briefly, hydrolysis liberates the pro-... 

In addition to and like innumerable other examples, these values are taken to reflect to some extent species differences in esterase activity and demonstrate how biological variability can complicate prodrug design. 

A variety of acyl groups other than acetyl have been used in prodrug design, several of which have already been presented in Chapt. 7. Branched and... 

When comparing the behavior of various esters of propranolol (8.72, R = H) in rat and dog plasma, liver microsomes and liver cytosol, the global trend emerged that the rates of hydrolysis decreased in the series linear alkanoates > cycloalkanoates > branched alkanoates [118][119]. Such an observation may be of interest to prodrug designers since it affords a continuum of foreseeable rates of activation. Furthermore, a clear substrate enantiose-lectivity was seen, in that hydrolysis of the (R)-propranolol esters was consistently faster than that of their antipodes. The same was true in mouse skin. 

There are few reports of 0- [(acyloxy)methy I1 derivatives in prodrug design. One example is that of salicylamide, whose 0-(acctoxymethyl), 0-[(butyryl-oxy)methyl], and 0-[(pivaloyloxy)methyl] derivatives (8.117, R = Me, Pr, and f-Bu, respectively) were examined for the kinetics and mechanism of their... 

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