Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/21592
Título: Unanticipated acyloxymethylation of sumatriptan indole nitrogen atom and its implications in prodrug design
Autor: Rodrigues, Tiago
Moreira, Rui
Guedes, Rita C.
Iley, Jim
Lopes, Francisca
Palavras-chave: Chemistry, Medicinal
Chemistry, Multidisciplinary
Pharmacology & Pharmacy
Data: 2008
Citação: Archiv der Pharmazie. 2008;341(6):344-350
Resumo: Sumatriptan is a potent and selective 5-HT1B and 5-HT1D agonist used in the symptomatic treatment of migraine; it shows poor oral bioavailability ascribed, in part, to its low lipophilicity. In an attempt to develop acyloxymethyl prodrugs of sumatriptan suitable for oral administration, we carried out the reaction of sumatriptan with chloromethyl esters. To our surprise, acyloxymethylation occurred preferentially at the indole nitrogen rather than at sulfonamide nitrogen, reflecting a difference either in product stability or in the nucleophilicities of the indole and sulfonamide anions. The hydrolysis of the corresponding N-1-acyloxymethyl derivatives was studied in aqueous buffers and in human plasma, by HPLC. N-1-Acyloxymethyl derivatives of sumatriptan are rapidly hydrolysed to the chemically stable N-1-hydroxymethylsumatriptan at pH 113. Slow formation of the parent drug was observed only at high pH values. Hydrolysis of sumatriptan derivatives is slower in human plasma than in phosphate buffer and also generates N-1-hydroxymethylsumatriptan rather than the parent drug. These results indicate that N-1-acyloxymethyl derivatives of sumatriptan cannot be considered as true prodrugs of sumatriptan.
URI: http://hdl.handle.net/10451/21592
DOI: http://dx.doi.org/10.1002/ardp.200700250
ISSN: 0365-6233
Versão do Editor: http://onlinelibrary.wiley.com/doi/10.1002/ardp.200700250/epdf
Aparece nas colecções:FF - Produção Científica 2000-2009

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