Alkyl ester prodrugs, hydrolysis

B. Steffansen, N. Mprk, H. Bundgaard, Prodrugs as Drug Delivery Systems. 95. Stability and Enzymatic Hydrolysis of Glycolate, Glycolamide and Alkyl Esters of Tyrosine , Acta Pharm. Nordica 1989, 2, 47-56. 

In Sect. 8.2.3, we have discussed 1-alkyl-l-azacycloalkan-2-ones (8.32, n = 1 or 2 m = 3, 4, 5 or 6) as a group of amidoalkyl esters, taking prodrugs of indomethacin (8.9, R = OH) and naproxen (8.26) as examples [43a,b]. For both compounds, the prodrugs in the series n = 1 were rapidly hydrolyzed (tm ca. 0.5-1 h in pH 7.4 buffer at 32°). Furthermore, the carbinolamides liberated were not fully stable and broke down by hydrolysis to produce the toxic formaldehyde (Fig. 8.3) [62], Thus, the half-life of decomposition of A-(hydroxymethyl)benzamide (HOCH2-NH-CO-C6H5), a pro-moiety of 8.56 discussed below, was 160 h at pH 7.4 and 37° [69]. This means that a small amount of formaldehyde may be formed in vivo. 

These compounds contain the fragment R as an alkyl or aryl moiety. In other words, they result from the esterification of an alcohol or a phenol with nitrous acid, nitric acid, phosphoric acid, sulfuric acid, or sulfamic acid, respectively. Many of the esters to be examined in this chapter must be activated prior to eliciting their effects, e.g., the organic nitrites and nitrates, which act as donors of nitric oxide or an analogous molecule, and phosphates, which are activated by hydrolysis or even by phosphorylation (antiviral agents). Sulfates are very seldom active or used as prodrugs, but they have significance as metabolites and as industrial xenobiotics. 

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