PMID: 9434286Jan 22, 1998Paper

Acyloxymethyl as a drug protecting group: Part 4. The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acid agents

Pharmaceutical Research
J IleyE Mendes

Abstract

Novel tertiary amidomethyl esters were synthesized and evaluated as potential prodrugs of carboxylic acid agents. The hydrolyses of the title compounds in buffer solutions and in plasma were studied by UV spectroscopy and HPLC. 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. Derivatives containing the ethyl hippurate carrier are useful prodrugs for ...Continue Reading

Citations

Mar 1, 2017·Archiv der Pharmazie·Arun RasheedAzeem Abdul Khareem
May 24, 2011·Journal of Drug Delivery·Bong-Seop LeeJohn S Yu
Sep 11, 2007·Chemistry : a European Journal·Andrew W PattersonJonathan A Ellman
Apr 26, 2005·International Journal of Pharmaceutics·Riku NiemiTomi Järvinen
Mar 29, 2008·Journal of the American Chemical Society·Xuechen Li, Samuel J Danishefsky
May 16, 2008·The Journal of Organic Chemistry·Andrew W PattersonJonathan A Ellman
Jan 6, 2000·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·J IleyS Souza
Nov 1, 2013·Bioconjugate Chemistry·Eric L SchneiderDaniel V Santi
Dec 23, 2020·The Journal of Organic Chemistry·Kosuke OhsawaTakayuki Doi
May 11, 2004·The Journal of Organic Chemistry·Emília ValenteJim Iley

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