Design, synthesis and evaluation of N-basic substituted 3-hydroxypyridin-4-ones: orally active iron chelators with lysosomotrophic potential.
To investigate the possibility of targeting chelators into the lysosomal iron pool, nine bidentate 3-hydroxypyridin-4-ones with basic chains have been synthesized. As the turnover of ferritin iron is centred in the lysosome, such strategy is predicted to increase chelator efficacy of bidentate ligands. The pKa values of the ligands together with their distribution coefficients between 1-octanol and 4-morpholinepropane sulphonic acid (MOPS) buffer pH 7.4 have been determined. The in-vivo iron mobilization efficacy of these basic 3-hydroxypyridin-4-ones has been investigated in a 59Fe-ferritin-loaded rat model. No obvious correlation was observed between efficacy and the pKa value of the side chain, although those with pKa > 7.0 tended to be more efficient than those with pKa < 7.0. The imidazole-containing molecules are much less effective than the tertiary amine derivatives. A dose-response study suggested that basic pyridinones are relatively more effective at lower doses when compared with N-alkyl hydroxypyridinones. Optimal effects were observed with the piperidine derivatives 4h and 4i. The derivative 4i at a dose of 150 micromol kg(-1) was more effective than 450 micromol kg(-1) deferiprone, the widely adopted clinical dose.
Liu
Z D
ZD
Department of Pharmacy, King's College London, UK.
Khodr
H H
HH
Lu
S L
SL
Hider
R C
RC
D000468:Alkalies; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D000077543:Deferiprone; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004341:Drug Evaluation; D005293:Ferritins / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D007502:Iron Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D007504:Iron Radioisotopes; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000468:Alkalies; D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D008024:Ligands; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D000077543:Deferiprone; D005293:Ferritins