Synthesis of 2-amido-3-hydroxypyridin-4(1H)-ones: novel iron chelators with enhanced pFe3+ values.
The synthesis of a range of 2-amido-3-hydroxypyridin-4-ones as bidentate iron(III) chelators with potential for oral administration is described. The pKa values of the ligands together with the stability constants of their iron(III) complexes have been determined. Results indicate that the introduction of an amido substituent at the 2-position leads to an appreciable enhancement of the pFe3+ values. The ability of these novel 3-hydroxypyridin-4-ones to facilitate the iron excretion in bile was investigated using a 59Fe-ferritin loaded rat model. The optimal effect was observed with the N-methyl amido derivative 15b, which has an associated pFe3+ value of 21.7, more than two orders of magnitude higher than that of deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one) 1a (pFe3+ = 19.4). Dose response studies suggest that chelators with high pFe3+ values scavenge iron more effectively at lower doses when compared with simple dialkyl substituted hydroxypyridinones.
Liu
Z D
ZD
Department of Pharmacy, King's College London, UK.
Piyamongkol
S
S
Liu
D Y
DY
Khodr
H H
HH
Lu
S L
SL
Hider
R C
RC
D000818:Animals; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000493:pharmacokinetics; D007501:Iron / Q000378:metabolism / Q000493:pharmacokinetics; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000378:metabolism; D007504:Iron Radioisotopes; D008024:Ligands; D008297:Male; D011728:Pyridones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D008024:Ligands; D011728:Pyridones; D005293:Ferritins; D007501:Iron