Prodrugs INDEX

Mahfouz, N. M., Omar, F. A., and Aboul-Fadl, T. Cyclic amide derivatives as potential prodrugs II. A-Hydroxymethylsuccinimide-/isatin esters of some NSAIDs as prodrugs with an improved therapeutic index. Eur. J. Med. Chem. 34(7—8) 551—562, 1999. 

Again, we found no evidence of acute toxicity. These data collectively indicate that the toxicity of DS-96 is a manifestation of its peak plasma concentrations, and suggest that a suitable prodrug of DS-96 may greatly widen the therapeutic index and margin of safety. 

Initial conversion is to 4-hydroxycyclophos-phamide, which is in spontaneous equilibrium with its tautomeric form, aldophosphamide. These function as inactive "transport" molecules (188). Subsequent spontaneous elimination of acrolein from aldophosphamide generates the active moiety, phosphoramide mustard. Because of its unique activation mechanism, numerous bioreversible prodrugs of phosphoramide mustard have been investigated in an attempt to improve its therapeutic index (189). 

Primary amides of carboxylic acids are easily converted to the corresponding acid (e.g. depamide, progabide) in humans and can thus be used in prodrug design. Amides of ketoprofen-derived arylacetic acids possess a therapeutic index one order of magnitude greater than that of indomethacin. ... 

Azacytidine (500) was reduced with sodium borohydride in hexamethyl phosphoramide followed by acidification to dihydro-5-azacytidine (501). The deuterated derivative (502) was made similarly from sodium borodeu-teride, Scheme 5.118.) [652, 653]. 5-Azacytidine (500) is an antitumour agent, effective against human acute myeloblastic leukaemia and acute lymphoblastic leukaemia. However, it is unstable in aqueous solution, so the stable dihydro derivative (501) was made. This is 30 x less potent than (500), but has the same spectrum of activity however it has a superior therapeutic index and is better able to cross the blood-brain barrier. It may be a prodrug for 5-azacytidine [654-658],... 

Boyer et al. synthesized and biologically evaluated a series of liver-selective phosphonic acids (PA) thyroid hormone receptor agonists (249) and their prodrugs to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. 

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