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Synthesis, stability and in vitro dermal evaluation of Aminocarbonyloxymethyl Esters as prodrugs of Carboxylic Acid Agents

Mendes, Eduarda; Furtado, Tania; Neres, Joao; Iley, Jim; Jarvinen, Tomi; Rautio, Jarkko and Moreira, Rui (2002). Synthesis, stability and in vitro dermal evaluation of Aminocarbonyloxymethyl Esters as prodrugs of Carboxylic Acid Agents. Bioorganic and Medicinal Chemistry, 10(3) pp. 809–816.

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Aminocarbonyloxymethyl esters 3 based on (S)-amino acid carriers were synthesised and evaluated as potential prodrugs of carboxylic acid agents. In addition, the compounds were evaluated as topical prodrugs with the aim of improving the dermal delivery of two non-steroidal anti-inflammatory agents: naproxen and flufenamic acid. The lipophilicities of these compounds were determined and their hydrolyses in aqueous solutions and in human plasma were examined. Compounds 3 containing a secondary carbamate group were hydrolysed at pH 7.4 by two different routes: (i) direct nucleophilic attack at the ester carbonyl carbon leading to the release of the parent carboxylic acid and (ii) intramolecular rearrangement involving an O!N acyl migration, leading to the formation of the corresponding amide. The rearrangement pathway is highly dependent on the size of the carboxylic acid and
amino acid substituents, being eliminated when the amino acid is valine or leucine. In contrast, compounds 3 decomposed in plasma exclusively through ester hydrolysis, most releasing the parent carboxylic acid quantitatively with half-lives shorter than 5 min. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro. All prodrugs evaluated exhibited a
lower flux than the corresponding parent carboxylic acid. The poor skin permeation observed for compounds 3 is most probably due to their low aqueous solubility and high partition coefficient.

Item Type: Journal Article
ISSN: 0968-0896
Extra Information: Some of the symbols may not have transferred correctly into this bibliographic record.
Keywords: NSAIDs; acyloxymethyl; prodrug
Academic Unit/Department: Science
Item ID: 4011
Depositing User: James Iley
Date Deposited: 04 Jul 2006
Last Modified: 14 Jan 2016 15:59
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