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Purpose. Novel tertiary amidomethyl esters were synthesized and evaluated as potential prodrugs of carboxylic acid agents.

Methods. The hydrolyses of the title compounds in buffer solutions and in plasma were studied by UV spectroscopy and HPLC.

Results. Amidomethyl esters were hydrolyzed by acid-catalyzed, base-catalyzed and pH-independent pathways. Both the acid-catalyzed, , and pH-independent processes, k_o, were strongly affected by the electronic and steric nature of the N-substituent in the pro-moiety. For both processes, the electronic effect exerted greater influence, and electron-withdrawing substituents retarded reaction. The pH-independent hydrolysis of amidomethyl esters were dependent on the pK_a of the carboxylate leaving group, giving a Brönsted β_lg value of −0.91. The base-catalyzed, , pathway was mainly affected by the steric bulk of the nitrogen …