caa a22 4500 477128440 CHVBK 20180405111656.0 cr unu---uuuuu 170330e19971101xx s 000 0 eng 10.1023/A:1012146905833 doi (NATIONALLICENCE)springer-10.1023/A:1012146905833 Acyloxymethyl as a Drug Protecting Group: Part 4. The Hydrolysis of Tertiary Amidomethyl Ester Prodrugs of Carboxylic Acid Agents [Elektronische Daten] [Jim Iley, Rui Moreira, Teresa Calheiros, Eduarda Mendes] 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, $${\rm{k}}_{{\rm{H}}^ + } $$ , 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 βlg value of −0.91. The base-catalyzed, $${\rm{k}}_{{\rm{OH}}^ - } $$ , 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. Plenum Publishing Corporation, 1997 amidomethylation nationallicence NSAIDs nationallicence valproic acid nationallicence clofibric acid nationallicence probenecid nationallicence prodrugs nationallicence mechanism of hydrolysis nationallicence Iley Jim E-mail: j.n.iley@open.ac.uk aut Moreira Rui E-mail: j.n.iley@ aut Calheiros Teresa aut Mendes Eduarda aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/11(1997-11-01), 1634-1639 0724-8741 14:11<1634 1997 14 11095 https://doi.org/10.1023/A:1012146905833 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012146905833 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Iley Jim E-mail: j.n.iley@open.ac.uk aut NATIONALLICENCE 700 1- Moreira Rui E-mail: j.n.iley@ aut NATIONALLICENCE 700 1- Calheiros Teresa aut NATIONALLICENCE 700 1- Mendes Eduarda aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/11(1997-11-01), 1634-1639 0724-8741 14:11<1634 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer