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Unanticipated acyloxymethylation of sumatriptan indole nitrogen atom and its implications in prodrug design

Rodrigues, Tiago; Moreira, Rui; Guedes, Rita C.; Iley, Jim and Lopes, Francisca (2008). Unanticipated acyloxymethylation of sumatriptan indole nitrogen atom and its implications in prodrug design. Archiv der Pharmazie, 341(6) pp. 344–350.

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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 N1-acyloxymethyl derivatives was studied in aqueous buffers and in human plasma, by HPLC. N1-Acyloxymethyl derivatives of sumatriptan are rapidly hydrolysed to the chemically stable N1-hydroxymethylsumatriptan at pH 1-13. 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 N1-hydroxymethylsumatriptan rather than the parent drug. These results indicate that N1-acyloxymethyl derivatives of sumatriptan cannot be considered as true prodrugs of sumatriptan.

Item Type: Journal Article
Copyright Holders: 2008 WILEY-VCH Verlag GmbH & Co.
ISSN: 1521-4184
Keywords: acyloxymethylation; indole; prodrugs; sumatriptan
Academic Unit/Department: Science
Item ID: 10818
Depositing User: James Iley
Date Deposited: 13 Jun 2008
Last Modified: 14 Jan 2016 16:58
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