Systematic comparison of the mono-, dimethyl- and trimethyl 3-hydroxy-4(1H)-pyridones – attempted optimization of the orally active iron chelator, deferiprone

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Abstract

Abstract A range of close analogues of deferiprone have been synthesised. The group includes mono-, di- and tri-methyl-3-hydroxy-4(1H)-pyridones. These compounds were found to possess similar pFe3+ values to that of deferiprone, with the exception of the 2.5-dimethylated derivatives. Surprisingly the NH-containing hydroxy-4(1H)-pyridones were found to be marginally more lipophilic than the corresponding N-Me containing analogues. This same group are also metabolised less efficiently by Phase 1 hydroxylating enzymes than the corresponding N-Me analogues. As result of this study, three compounds have been identified for further investigation centred on neutropenia and agranulocytosis.
Original languageEnglish
JournalEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Early online date5 Mar 2016
DOIs
Publication statusE-pub ahead of print - 5 Mar 2016

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