title: Hydrolytic and metabolic characteristics of the esters of 1-(3'-hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41), potentially useful iron chelators.
abstract: 1-(3'-Hydroxypropyl)-2-methyl-3-hydroxypyridin-4-one (CP41) has been extensively investigated as an orally effective iron chelator. In order to improve the pharmacokinetic and metabolic properties of CP41, eleven aromatic esters have been synthesised and tested as potential prodrugs. In the present study, the hydrolytic rates of these CP41 esters in phosphate buffer (pH2.0 and pH 7.4), rat blood and rat liver homogenate have been determined and found to cover a wide range. Generally, they possessed relatively slow hydrolytic rates in phosphate buffer (0-50 nmol/ml/hr at pH 2.0 and 0-140 nmol/ml/hr at pH 7.4). The hydrolytic rates in rat blood fell in the range of 9-5766 nmol/ml blood/hr and in rat liver homogenate 1-800 micromol/g liver tissue/hr. All esters possess a higher lipophilicity than that of the parent compound CP41. Although no apparent relationship was observed between the lipophilicities and hydrolytic rates, the esters with relatively higher hydrolytic rates in liver homogenate tend to possess higher iron scavenging efficacies. Further investigation of the metabolism of selected CP41 esters indicates that metabolism is a key factor influencing the efficacy of CP41 esters, as some esters can be metabolically inactivated in the liver in preference to undergoing ester hydrolysis. Ester design, combined with a knowledge of the prodrug metabolism, is a useful strategy for the production of 3-hydroxypyridin-4-ones with enhanced iron scavenging efficacy.
authors.affiliation: Department of Pharmacy, King's College London, University of London, UK.
authors.forename: D Y
authors.initials: DY
authors.lastname: Liu
authors.forename: Z D
authors.initials: ZD
authors.lastname: Liu
authors.forename: S L
authors.initials: SL
authors.lastname: Lu
authors.forename: R C
authors.initials: RC
authors.lastname: Hider
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D006868:Hydrolysis; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C121031:3-hydroxypyridin-4-one; D007502:Iron Chelating Agents; D011355:Prodrugs; D011725:Pyridines; D011728:Pyridones