Design, synthesis, and biological evaluation of aromatic ester prodrugs of 1-(3'-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41) as orally active iron chelators.
In order to improve chelation efficacy and to minimise toxicity, eleven aromatic ester prodrugs of 1-(3'-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41) have been synthesised. The distribution coefficients of these ester prodrugs between 1-octanol and MOPS buffer pH 7.4 were measured together with their rates of hydrolysis at pH 2 and pH 7.4, in rat blood and liver homogenate. The biliary metabolic profiles of selected ester prodrugs were investigated in rats. The in vivo iron mobilisation efficacy of these ester prodrugs has been compared with that of the parent drug using a 59Fe-ferritin loaded rat model. The hydrolytic rates of these esters vary appreciably, esters with heteroaromatic acid moieties being less stable than the corresponding benzoyl analogues. Many prodrugs were found to enhance the ability of the parent hydroxypyridinone to facilitate 59Fe excretion, the optimal effect being observed with the 4-methylbenzoyl ester derivative 8d. However, not all prodrugs provide an increased efficacy, indicating that lipophilicity is not the only factor which influences drug efficacy. Furthermore no clear correlation between lipophilicity, susceptibility towards hydrolysis and efficacy was detected.
Liu
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ZD
Department of Pharmacy, King's College London, UK.
Liu
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DY
Lu
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Hider
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RC
D000818:Animals; D001646:Bile / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D007504:Iron Radioisotopes; D008099:Liver / Q000166:cytology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D011355:Prodrugs; D011728:Pyridones; C108009:CP 41