title: Synthesis, stability and in vitro dermal evaluation of aminocarbonyloxymethyl esters as prodrugs of carboxylic acid agents.
abstract: Aminocarbonyloxymethyl esters 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 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 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 is most probably due to their low aqueous solubility and high partition coefficient.
authors.affiliation: CECF, Faculdade de Farmácia da Universidade de Lisboa, 1699 Lisbon Codex, Portugal. ermendes@ff.ul.pt
authors.forename: Eduarda
authors.initials: E
authors.lastname: Mendes
authors.forename: Tânia
authors.initials: T
authors.lastname: Furtado
authors.forename: João
authors.initials: J
authors.lastname: Neres
authors.forename: Jim
authors.initials: J
authors.lastname: Iley
authors.forename: Tomi
authors.initials: T
authors.lastname: Jarvinen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D010949:Plasma / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism
chemical_list: D000588:Amines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004337:Drug Carriers; D004952:Esters; D011355:Prodrugs