title: Characterisation of a novel oral iron chelator: 1-(N-Acetyl-6-Aminohexyl)-3-Hydroxy-2-Methylpyridin-4-one.
abstract: OBJECTIVE
  Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are iron chelators currently in clinical use for the treatment of iron overload. Due to difficulties with administration and associated side effects with these three molecules, the search continues for an efficient nontoxic orally active iron chelator. This communication describes the properties of one such candidate, 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1).
  
  
  METHODS
  Physicochemical characterisation techniques, including partition coefficient, pKa values and logK values for iron(III). Iron scavenging assays, from iron citrate, nontransferrin bound iron and iron-loaded rats. Cytotoxicity studies using white cells, hepatocytes and cardiomyocytes.
  
  
  RESULTS
  CM1 possesses high affinity and selectivity for iron(III) and a suitable partition coefficient to permeate membranes. CM1 forms a neutral 3 : 1 iron(III) complex under physiological conditions and so, it is predicted to be capable of entry into mammalian cells to scavenge excess intracellular iron and to efflux from cells as the neutral 3 : 1 complex. CM1 is demonstrated to be orally active and to possess a higher efficacy than DFP in rats. CM1 displays no toxicity to a range of cell types.
  
  
  CONCLUSIONS
  The above promising studies will be extended to monitor the pharmacokinetics and metabolism of CM1. CM1 is an excellent candidate for phase 1 clinical trials.
authors: Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; College of Medicine and Public Health, Ubon Ratchathani University, Chiang Mai, Thailand.
authors: Kanjana
authors: K
authors: Pangjit
authors: Ratana
authors: R
authors: Banjerdpongchai
authors: Chada
authors: C
authors: Phisalaphong
authors: Suthat
authors: S
authors: Fucharoen
authors: Yuan Yuan
authors: YY
authors: Xie
authors: Zi Dong
authors: ZD
authors: Lu
authors: Robert C
authors: RC
authors: Hider
authors: Somdet
authors: S
authors: Srichairatanakool
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007501:Iron / Q000097:blood / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D019190:Iron Overload / Q000188:drug therapy; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013379:Substrate Specificity
chemical_list: C000607906:1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one; D000081:Acetamides; D007502:Iron Chelating Agents; D011728:Pyridones; D007501:Iron
keywords: hydroxypyridin-4-one; iron chelator; iron overload; oral activity; thalassaemia