Acyloxymethyl as a drug protecting group: Part 4. The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acid agents.
OBJECTIVE
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, kH+, and pH-independent processes, ko, 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 pKa of the carboxylate leaving group, giving a Brönsted beta(1g) value -0.91. The base-catalyzed, kOH-, pathway was mainly affected by the steric bulk of the nitrogen substituents in the amide moiety, the reactivity being reduced with larger N-substituents. Hydrolysis in human plasma appeared to be mediated by enzymic processes and is dependent upon the steric bulk in the carboxylic acid moiety. Plasma hydrolysis rates were inversely dependent on the lipophilicity of the ester.


CONCLUSIONS
Derivatives containing the ethyl hippurate carrier are useful prodrugs for carboxylic acid-containing drugs with pKa > 3.5, such as non-steroidal anti-inflammatory agents and valproic acid.
Iley
J
J
Chemistry Department, Open University, Milton Keynes, United Kingdom. j.n.iley@open.ac.uk
Moreira
R
R
Calheiros
T
T
Mendes
E
E
D000577:Amides / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D002264:Carboxylic Acids / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D015195:Drug Design; D004355:Drug Stability; D004952:Esters; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*
D000577:Amides; D002264:Carboxylic Acids; D004952:Esters; D011355:Prodrugs