title: Systematic comparison of the mono-, dimethyl- and trimethyl 3-hydroxy-4(1H)-pyridones - Attempted optimization of the orally active iron chelator, deferiprone.
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 pFe(3+) 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.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Xie
authors.affiliation: Institute of Pharmaceutical Science, King's College London, UK.
authors.forename: Zidong
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Institute of Pharmaceutical Science, King's College London, UK.
authors.forename: Xiao-Le
authors.initials: XL
authors.lastname: Kong
authors.affiliation: School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Institute of Pharmaceutical Science, King's College London, UK.
authors.forename: Sukhi
authors.initials: S
authors.lastname: Bansal
authors.affiliation: Institute of Pharmaceutical Science, King's College London, UK. Electronic address: robert.hider@kcl.ac.uk.
authors.forename: Robert
authors.initials: R
authors.lastname: Hider
mesh_terms: D000284:Administration, Oral; D000077543:Deferiprone; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism
chemical_list: C000612784:3-hydroxy-4(1H)-pyridone; D007502:Iron Chelating Agents; D011728:Pyridones; D000077543:Deferiprone
keywords: HPO; Iron(III)chelator; Orally active