Prodrugs redox system

Figure 16.2 Dihydropyridine-pyridinium salt redox system for site-specific and sustained delivery to the brain. The prodrug A is delivered directly to the brain, where it is oxidized and trapped as the prodrug B. The quaternary ammonium salt is slowly cleaved by chemical/enzymatic action with sustained release of the biologically active phenylethylamine C and the facile elimination of the carrier molecule D. Elimination of the drug from the general circulation is by comparison accelerated, either as A or B or as cleavage products...

The bioactivation process is exclusively hydrolytic for carrier prodrugs it involves mostly redox systems for bioprecursors. 

A redox system (50/51) to affect brain delivery of y-aminobutyric acid (GABA) derivatives and analogues was also developed. Zincke reaction of 41 with acetal 49 followed by dithionite reduction afforded the 1,4-dihydropyridine prodrug 50, which was hydrolyzed and oxidized in vivo to the active GABA analogue 51. The neutral and lipophilic 1,4-dihydropyridine 50 can penetrate the blood-brain barrier (BBB), whereas the oxidized pyridinium salt 51 is retained in the brain for an extended period and then eliminated. 

Tissue targeting may also be directed at tumors through the use of monoclonal antibodies, as briefly mentioned earlier. Finally, brain targeting can also be attempted with the prodrug approach, as exemplified by estradiol by use of a redox-based chemical delivery system (174). 

Generalizing the dihydropyridine pyridinium salt redox delivery system, successfully applied to 2-PAM, Bodor and his coworkers proposed an astute sustained release methodology for brain delivery, based on the mixed-t3q)e prodrugs. The biologically active compound is linked to a... 

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