Carbamoylmethyl ester prodrugs

Variously N-substituted glycolamide esters (TV-substituted carbamoylmethyl esters) of carboxylic acids have been proposed as prodrugs of particular... 

The case of aspirin in Table 8.3 is of special interest. Indeed, its acetyl ester group is particularly labile to enzymatic and nonenzymatic hydrolysis (see Sect. 7.4), and the reaction is even faster when the carboxy group is neutralized by esterification. A true ester prodrug of acetylsalicylic acid must fulfill the condition that its hydrolysis liberates aspirin rather than a prodrug of salicylic acid. An investigation of several aspirin prodrugs confirmed the interest of carbamoylmethyl esters and showed the (ATV-diethylcarbamoyl)methyl ester (Table 8.3) to liberate the highest proportion (ca. 60%) of aspirin [37], In... 

A comparison between carbamoylmethyl and aminoalkyl esters has been reported for a small series of prodrugs of ibuprofen (8.28) [39]. A further interest of this work is the systematic comparison made between the enantiomers of ibuprofen, i. e., the active (+)-(S)-form and the inactive (-)-(/ )-form. As shown in Table 8.4, the ethyl esters were hydrolyzed very slowly in human plasma, with t1/2 values in the order of 100 - 200 h. In contrast, the hydrolysis of the carbamoylmethyl and aminoalkyl esters occurred with t1/2 values in the order of some or several minutes. The carbamoylmethyl esters were hydrolyzed very rapidly with low substrate enantioselectivity, while the 2-(imidazol-l-yl)ethyl esters were hydrolyzed somewhat more slowly and with marked substrate enantioselectivity. 

R = Me, Et, and PhCH2, respectively Fig. 8.1). In 80% human plasma at pH 7.4 and 37°, these model prodrugs were hydrolyzed with tm values of 3.5, 16, and 2.6 min, respectively [59]. Such rates of enzymatic hydrolysis are comparable to those of various carbamoylmethyl esters of benzoic acid (Table 8.2). It is important to note that the direct liberation of benzoic acid by Reaction a (Fig. 8.1) was severalfold faster than the competitive Reaction b. Reaction c was very slow in human plasma (tm > 100 h). In HO -catalyzed hydrolysis, the opposite regioselectivity was seen, with the terminal ester bridge being cleaved markedly faster than the central one. No data appears to be available on chemical hydrolysis at neutral pH. 

Since the use of human plasma as a model for skin esterases is debatable, the relevance of the biological results in Table 8.6 need validation as far as skin delivery is concerned. Indeed, permeation experiments across excised human skin showed that administration of prodrugs markedly improved the cutaneous delivery of nalidixic acid, with complete hydrolysis of the (acyl-oxy)methyl esters and significant, albeit incomplete, hydrolysis of the methyl and carbamoylmethyl esters [64],... 

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