Amidate esters/prodrugs

Bodor and Brewster (1983) first used the term CDS, in describing the use of dihydropyridine ester- (or amide)-linked prodrugs such as 27 (X-OH is the parent) which can partition readily into the CNS, there to be oxidized to pyridinium salts (28), which are effectively trapped in the biophase because of their extreme polarity, and which then undergo enzymic or chemical hydrolysis of the now very labile ester link to release active drug. 

Fig. 8.20. Two-step activation ofN-[(acyloxy)methyl] prodrugs, a) Cleavage of the ester bond, which may be enzymatic and/or nonenzymatic, is followed by decomposition of the N-(hy-droxymethyl) intermediate, b) For (V-(hydroxymethyl) derivatives of amides and imides, the decomposition is base-catalyzed, c) For N-(hydroxymethyl) derivatives of amines, the decomposition can be uncatalyzed or undergo acid or base catalysis (modified from [214]).

The 3-(2-hydroxy-4,6-dimethylphenyl)-3-methylbutanoic acid shown in Fig. 8.23, as well as another phenylpropanoic derivative presented below, have been used as pro-moieties to prepare a number of prodrugs of therapeutic peptides [169] [238], Of interest here is that the pro-moiety is linked to the peptide by both amide and ester bonds to form a cyclic, double prodrug, the two-step activation of which is schematized in Fig. 8.24. Briefly, enzymatic hydrolysis of the ester bond unmasks a nucleophile (in this case, a phenol) that carries out an intramolecular attack on the amide bond, resulting in cy-clization of the pro-moiety and elimination of the peptide. [Leu5]enkephalin was one of the therapeutic peptides used to validate the concept, as illustrated in Fig. 8.25 [241],... 

H. Bundgaard, N. M. Nielsen, A. Buur, Aspirin Prodrugs Synthesis and Hydrolysis of 2-Acetoxybenzoate Esters of Various V-(Hydroxyalkyl)amides , Int. J. Pharm. 1988, 44, 151-158. 

F. A. Omar, Cyclic Amide Derivatives as Potential Prodrugs. Synthesis and Evaluation of V-Hydroxymethylphthalimide Esters of Some Non-Steroidal Anti-Inflammatory Car-boxy he Acid Drugs , Eur. J. Med. Chem. 1998, 33, 123-131. 

Prodrugs are drug substances that are biotransformed in the body to active metabolites and chemotherapeutic agents. Examples include sulfasalazine to sul-fapyridine, phenylbutazone to oxy-phenbutazone, aspirin to salicylate, and heta-cillin to ampicillin. In some cases, such as aspirin (ester) and hetacillin (amide), hydrolysis in water releases the active drug moiety contained within the basic structure of the prodrug. 

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. 

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