In vivo evaluation of hydroxypyridone iron chelators in a mouse model.
The 59Fe excretion caused by a range of bidentate N-substituted [R group = methyl (CP20), ethyl (CP21), propyl (CP22), isopropyl (CP23), butyl (CP24) or hexyl (CP25)] 3-hydroxypyrid-4-one chelators in iron-overloaded mice is presented. All the compounds cause significant iron excretion when given intraperitoneally, but that the most hydrophobic compounds, CP24 and CP25, were toxic except at low doses. The excretion caused by CP21, CP22 and CP23 were significantly greater than that caused by CP20 and slightly larger than that caused by an equivalent dose of desferrioxamine. These compounds (CP20 through CP24) also caused significant excretion of 59Fe when administered orally. Compounds CP21, CP22 and CP24 were significantly more active than compounds CP20 and CP23. It is concluded that the N-ethyl or N-propyl 3-hydroxypyrid-4-ones are the most promising compounds for clinical application. Preliminary experiments using a hexadentate pyrid-2-one, CP130, show that this causes significant 59Fe excretion both when given intraperitoneally or orally.
D000284:Administration, Oral; D000818:Animals; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007501:Iron / Q000652:urine; D007502:Iron Chelating Agents / Q000494:pharmacology*; D051379:Mice; D011728:Pyridones / Q000494:pharmacology*
D007502:Iron Chelating Agents; D011728:Pyridones; D007501:Iron; D003676:Deferoxamine