Document Detail

Acyloxymethyl as a drug protecting group: Part 4. The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acid agents.
MedLine Citation:
PMID:  9434286     Owner:  NLM     Status:  MEDLINE    
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, 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.
J Iley; R Moreira; T Calheiros; E Mendes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Pharmaceutical research     Volume:  14     ISSN:  0724-8741     ISO Abbreviation:  Pharm. Res.     Publication Date:  1997 Nov 
Date Detail:
Created Date:  1998-02-19     Completed Date:  1998-02-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8406521     Medline TA:  Pharm Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1634-9     Citation Subset:  IM    
Chemistry Department, Open University, Milton Keynes, United Kingdom.
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MeSH Terms
Amides / blood,  chemistry,  metabolism*
Carboxylic Acids / blood,  chemistry,  metabolism*
Drug Design
Drug Stability
Hydrogen-Ion Concentration
Prodrugs / chemical synthesis,  chemistry,  metabolism*
Reg. No./Substance:
0/Amides; 0/Carboxylic Acids; 0/Esters; 0/Prodrugs

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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