Bioprecursor prodrugs

As indicated above, bioprecursor prodrugs do not contain a carrier or promoiety but rather contain a latent functionality that is metabolically or chemically transformed to the active drug molecule. The types of activation often involve oxidative activation, reductive activation, phosphorylation, and in some cases chemical activation. Of these, oxidation is commonly. seen, since a number of endogenous enzymes can carry out these transformations. Phosphorylation has been widely exploited in the development of antiviral agents, and many currently available agents depend on this type of activation. 

The abundance of oxidizing enzymes in the body has made this type of bioaclivation a popular route. Isozymes of cytochrome P-4S0 can oxidize a wide variety of functionalities. generally to produce more polar compounds that can be excreted directly or undergo phase 2 conjugation reactions and. subsequently undergo elimination. This occurs in a fairly predictable manner and, therefore, has been successfully exploited in prodrug approaches. 

sphorylation is commonly required for the bioactivation of antiviral agents. The.se agents ate commonly nucleosides. which mu.st be converted to the nucleotides to have 

In addition to the selective toxicity mentioned, the prodrug approach offers the additional advantage of increased cell penetration. The prodrug can easily enter the cell via active 

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Bioprecursor prodrugs are compounds that already contain the embryo of the active species within their structure. This active species is liberated by metabolism of the prodrug (Figure 9.5). 

A typical example of an effective bioprecursor prodrug is given by the anti-inflammatory drug sulindac. Sulindac, di-5-fluoro-2-methyl-l-[p-(methylsulfinyl) benzylidene] indene-3 acetic acid is a non-steroidal anti-inflammatory agent having a broad spectrum of activity in animal models and in man. The two quantitatively significant biotransformations undergone by sulindac in laboratory species and... 

The following examples illustrate the bioprecursor-prodrug approach, although the intentional use of bioprecursor design is relatively recent and, in some cases, there are some doubts about the prospective or the retrospective character of the design. The hrst examples relate to oxidative bioactivations they are followed by examples of reductive bioactivations and dually by non-redox reactions. Often, however, the active species results from a cascade of metabolic reactions involving oxidative as well as reductive processes, complicated by hydrolytic reactions or hydration-dehydration sequences. 

A simple example of a bioprecursor prodrug is found in dexpanthenol and 3-pyridine-methanol (Figure 36.27). These... 

Losartan is a non-peptide angiotensin 11 receptor antagonist used as an antihypertensive medication.It can also be considered as a bioprecursor prodrug insofar that, in vivo, the primary alcohol is oxidized to a carboxylic acid (Figure 36.28), which represents the actual active principle. ... 

III The Bioprecursor-Prodrug Principle 563 B Arylacetic acids from aroylpropionic ... 

VII Bioprecursor Prodrugs Application Examples 575 1 GENERAL INTRODUCTION ... 

A simple example of bioprecursor prodrug is found in dexpanthenol and 3-pyridine-methanol (Fig. 33.26). These primary alcohols are the reduced forms of the vitaminic factors pantothenic acid and nicotinic acid, respectively. Dexpanthenol has the advantage over the parent drug of being more stable, especially towards racemization. 

Fig. 33.37 The hexenoic analogue of indomethacin as bioprecursor prodrug of indomethacin.

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