Design bioprecursors

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. 

Wermuth, C.G. Designing prodrugs and bioprecursors. In Drug Design Fact or Fantasy Jolles, G., Woolridge, K.R.H., Eds. Academic Press London, 1984 47-72. 

Wermuth, C. G., Gaignault, J.-C., Marchandeau, C. Designing prodrugs and bioprecursors 1 carrier prodrugs. In The Practice of Medicinal Chemistry (Wermuth, C. G., Ed.). Academic Press London, 1996, pp. 671-696. 

This information was used to design bucloxic acid, fenbufene and furobufene, which are all bioprecursor forms of anti-inflammatory arylacetic acids (Fig. 33.36). For all these compounds the bioactivation takes place through a multistep process implying reductive, oxidative and hydration-dehydration sequences. 

The design of bioprecursors, which represents a creative application of the active metabolite concept in the forward-looking way, seems a priori more adequate for CNS delivery, but it still has to prove the reality of its clinical usefulness. 

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