Cascade prodrug

V Use of Cascade Prodrugs 571 A Bioprecursors versus carrier prodrugs 579... 

Fig. 9.8. Reaction cascade in the activation of (phosphoryloxy)methyl carbonates and carbamates (X = O or NH, respectively) as potential prodrugs of alcohols, phenols, and amines... 

Fig. 9.8 presents another, more complex type of phosphate prodrugs, namely (phosphoryloxy)methyl carbonates and carbamates (9-26, X = O or NH, resp.) [84], Here, the [(phosphoryloxy)methyl]carbonyl carrier appears quite versatile and of potential interest to prepare prodrugs of alcohols, phenols, and amines. The cascade of reactions leading from prodrug to drug as shown in Fig. 9.8 involves three steps, namely ester hydrolysis, release of formaldehyde, and a final step of carbonate hydrolysis (X = O) or A-decar-boxylation (X = NH). Three model compounds, a secondary alcohol, a primary aliphatic amine, and a primary aromatic amine, were derivatized with the carrier moiety and examined for their rates of breakdown [84], The alcohol, indan-2-ol, yielded a carrier-linked derivative that proved relatively... 

There are currently four racemic PPIs available on the market omeprazole, lansoprazole, pantoprazole, and rabeprazole. (More recently, enantiomerically pure versions have also been studied and developed, e.g., S-omeprazole, marketed by AstraZeneca as esomeprazole see Chapter II-2.) Proton pump inhibitors share the same core structure, the substituted pyridylmethyl-sulfmyl-benzimidazole, but differ in terms of substituents on this core structure. The absolute requirements of the core structure for the activity of PPIs was not understood until it became clear that the active PPIs are derived from inactive prodrugs the prodrugs are transformed, in the acid-secreting parietal cells, by a unique cascade of chemical structural transformations leading to the active principle, a cyclic sulfenamide species. Inhibition of acid secretion in turn is then achieved by formation of covalent disulfide bonds with key cysteines of the (H+/K+)-ATPase. 

A more recent application of oxime derivatives as prodrugs is the design of cascade prodmgs of dopamine agonists for the treatment of Parkinson s disease. As shown in Scheme 16, enones such as S-(-)-6-(Af,Af-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2//-naphthalen-l-one (103) can be oxidized in vivo to catecholamines... 

The concept, also called distal hydrolysis or the double prodrug concept, is illustrated by the use of 2-acyloxymethylbenzoic acids as amine protective functions, providing amides with the lability of esters (Figure 36.18a) and by the use of substituted vinyl esters [= (2-oxo-l,3-dioxol-yl)methyl esters] as lipophilic cascade carriers for carboxylic acid-containing drugs such as ampicillin or a-methyldopa or various cephalosporins (Figure 36.18b). 

Amsberry and Borchardt" " have applied Cain s cascade concept to prepare lipophilic polypeptide prodrugs. The amine functionality of the polypeptide is coupled to 2 -acylated derivatives of 3-(2, 5 -dihydroxy-4, 6 -dimeth-ylphenyl)-3,3-dimethylpropionic acid (Figure 36.23). Under simulated physiological conditions the parent amine is regenerated in a two-step process enzymatic hydrolysis of the phenolic ester, followed by a non-enzymatic intramolecular cyclization, leading to the release of the free amine (polypeptide) and a lactone. 

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. 

The kinetics of 5-fluorouracil and its metabolites are essentially nonlinear. Therefore it is extremely difficult to build models that would correctly describe the cascade of nonlinear transformations that are observed, starting from drug absorption to its transformation into the active moiety. More recently, capecit-abine has been commercialized. It is a fluor-pyrimidine carbamate available for oral administration. Concentrations of 5-fluorouracil in some tumors are higher than those in the adjacent healthy tissues. The tumor preferential activation of capecitabine to 5-fluorouracil is explained by tissue differences in the activity of cytidine deaminase and thymidine phos-phorylase. It is interesting to note that the last of the three metabolic steps leading to 5-fluorouracil is the formation of 5 -deoxy-5-fluori-dine. Capecitabine is thus a pro-prodrug (176-178). 

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