Synthesis, Stability and In Vitro Dermal Evaluation of Aminocarbonyloxymethyl Esters as Prodrugs of Carboxylic Acid Agents Eduarda Mendes, a, * Taˆnia Furtado, a Joa˜o Neres, a Jim Iley, b Tomi Jarvinen, c Jarkko Rautio c and Rui Moreira a a CECF, Faculdade de Farma ´cia da Universidade de Lisboa, 1699 Lisboa Codex, Portugal b Chemistry Department, The Open University, Walton Hall, Milton Keynes MK7 6AA, UK c Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, Fin-70211 Kuopio, Finland Received 6 July 2001; accepted 21 September 2001 Abstract—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. # 2002 Elsevier Science Ltd. All rights reserved. Introduction Many drugs containing the carboxylic acid group are poorly absorbed from the gastrointestinal (GI) tract as a result of unfavourable physicochemical properties. 1 The prodrug strategy has been widely used to improve oral delivery of such drugs by appropriate modulation of properties, such as lipophilicity and aqueous solubi- lity. 2 Moreover, for non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen and diclofenac, which contain the carboxylic acid functional group, the prodrug concept has also been used to minimise the GI side effects that constitute the most frequent adverse reactions of this class of drug. 3 6 Further, for NSAIDs, topical application can be considered as an alternative delivery method to oral use, especially in the treatment of local inflammatory and pain processes, where a high local drug concentration is needed. 79 However, because most NSAIDs also display limited skin per- meation, the prodrug approach has also been suggested as an attractive method of enhancing the skin perme- ability of several members of this drug class such as naproxen and ketoprofen. 10 13 A commonly used prodrug approach is to prepare acy- loxymethyl derivatives 1. These offer the possibility of modulating the rate of release of the parent drug and simultaneously modifying the physicochemical proper- ties, such as water solubility and lipophilicity, by vary- ing the R group in the acyl pro-moiety. However, neutral acyloxymethyl ester prodrugs 1 still present oral and dermal delivery problems due to very low water solubility and very high lipid solubility. For example, a- (acyloxy)alkyl esters of neutral b-lactam antibiotics are inefficiently absorbed from the GI tract 14 and thus taken orally are poorly active because they have very low aqueous solubility. It has also been recently repor- ted that acyloxymethyl esters of naproxen present low 0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(01)00336-4 Bioorganic & Medicinal Chemistry 10 (2002) 809–816 *Corresponding author. Tel.: +351-21-7946-413; fax: +351-21-7946- 470; e-mail: ermendes@ff.ul.pt