Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/21593
Título: Aminocarbonyloxymethyl ester prodrugs of flufenamic acid and diclofenac
Suppressing the rearrangement pathway in aqueous media
Autor: Ribeiro, Lina
Silva, Nuno
Iley, Jim
Rautio, Jarkko
Jarvinen, Tomi
Mota-Filipe, Helder
Moreira, Rui
Mendes, Eduarda
Palavras-chave: Chemistry, Medicinal
Chemistry, Multidisciplinary
Pharmacology & Pharmacy
Data: 2007
Editora: WILEY-V C H VERLAG GMBH
Citação: ARCHIV DER PHARMAZIE. - Vol. 340, n. 1 (JAN 2007), p. 32-40
Resumo: Aminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an 0 - N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to undergo rearrangement. These compounds were prepared in reasonable yield by a four-step synthetic method that uses the appropriate N-Boc-protected amino acid N-hydroxysuccinimide ester and secondary amine and chloromethyl chloroformate as key reactants. Their reactivity in pH 7.4 buffer and 80% human plasma at 37 degrees C was assessed by RP-HPLC. The aminocarbonyloxymethyl esters containing a secondary carbamate group derived from amino acids such as glycine or phenylalanine were hydrolyzed quantitatively to the parent drug both in non-enzymatic and enzymatic conditions, with no rearrangement product being detected. The oral bioavailability in rats was determined for selected diclofenac derivatives. These derivatives displayed a bioavailability of 25 to 68% relative to that of diclofenac, probably due to their poor aqueous solubility and lipophilicity. These results suggest that further optimization of aminocarbonyloxymethyl esters as potential prodrugs for non-steroidal anti-inflammatory drugs require the use of amino acid carriers with ionizable groups to improve aqueous solubility.
URI: http://hdl.handle.net/10451/21593
DOI: http://dx.doi.org/10.1002/ardp.200600145
ISSN: 0365-6233
Aparece nas colecções:FF - Produção Científica 2000-2009

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