Prodrug design, examples

Appropriately designed prodrugs, for example, phosphonoamidates (Lee et al. 2005), may allow acyclic nucleoside phosphonates such as tenofovir to be specifically targeted at tissues, that is, lymphatic tissue, where the virus (i.e., HIV) replicates. This principle has been recently extended to another nucleotide analogue, GS-9148 (Cmiar et al. 2008) and its phosphonoamidate prodrug, GS-9131 (Ray et al. 2008). 

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. 

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. 

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. 

Another feature of diacids of interest in prodrug design is that the free carboxy group of a drug R-COOH can be used to attach an additional carrier group R OH, e.g., R-CO-Cf -Cf -CO-OR. An example of this type has been reported for a lipid conjugate of testosterone, with R = 2-(l,3-dipalmi-toyljglyccryl [133] (see also Sect. 8.2.5). 

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... 

Thus, it s no wonder so many medicinal chemists are critical of prodrugs. However, and this is our conclusion, a lucid view cannot ignore the potential benefit, in this case the mere existence of a number of successful prodrugs. Nabumetone, oseltamivir, and pivampicilline are just a few examples that come to mind. They demonstrate that in a number of cases, prodrug design may indeed allow the separate optimization of PK and PD properties. 

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. 

The concepts and examples presented here are meant to clarify the objectives of a prodrug strategy, to exemplify the major chemical moieties used in prodrug design, and to illustrate the biochemical pathways involved in prodrug activation (i.e., hydrolysis, oxidation, or reduction). More detailed information can be found in a number of reviews [1-15]. 

Table 20.2 Examples of common and less common carrier groups used in prodrug design.

Prodrugs also occur in the organism. As an example of an endogenous prodrug, proinsulin is synthesized in the pancreas to be released as its active moiety insulin and an inactive propeptide. To some extent, the bioactivation of neurotransmitters could also be termed prodrug design by nature and there are many other examples in the realm of mammalian... 

This clearly indicates that the nature of the bond between the carrier and the active moiety plays a major role in prodrug design and that pharmacokinetic considerations are of utmost importance in this context. In the following paragraphs, some typical kinds of chemical bonds are discussed. It is not intended here to present an overview on this subject, but only to give some examples of how chemistry and pharmacokinetics interact in the field of prodrugs. 

For prodrugs, the situation is basically different because, in most cases, the chemical bond between transport moiety and active moiety is designed as labile to avoid, for example, urinary elimination of the prodrug, which would diminish the amount of active compound available at the site of action. However, this is not an inviolate rule, particularly if prodrug design is used to provide "slow formation" of the active moiety. 

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