CN128: A New Orally Active Hydroxypyridinone Iron Chelator
- 25 March 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (8), 4215-4226
- https://doi.org/10.1021/acs.jmedchem.0c00137
Abstract
Deferoxamine, deferiprone and deferasirox, are used for the treatment of systemic iron overload, although they possess limitations due to lack of oral activity, lower efficacy and side effects. These limitations led to a search for an orally active iron chelator with an improved therapeutic index. The lower efficacy of deferiprone is due to rapid glucuronidation leading to the formation of a non-chelating metabolite. Here, we demonstrate that the influence of metabolism can be reduced by introducing a sacrificial site for glucuronidation. A logP-guided investigation of 20 hydroxpyridinones led to the identification of CN128. The Fe(III) affinity and metal selectivity of CN128 are similar to those of deferiprone, the logP value is more lipophilic, and its iron scavenging ability is superior. Overall, CN128 was demonstrated to be safe in a range of toxicity assessments and is now in clinical trials for the treatment of β-thalassemia after regular blood transfusion.Keywords
Funding Information
- Ministry of Science and Technology of the People's Republic of China (2017YFE0102200)
- National Natural Science Foundation of China (81673291)
- Alzheimer's and Aging Research Center
This publication has 36 references indexed in Scilit:
- Design and Synthesis of Fluorinated Iron Chelators for Metabolic Study and Brain UptakeJournal of Medicinal Chemistry, 2012
- The Fenton Activity of Iron(III) in the Presence of DeferiproneJournal of Pharmaceutical Sciences, 2008
- Fenton Chemistry and Iron Chelation under Physiologically Relevant Conditions: Electrochemistry and KineticsChemical Research in Toxicology, 2006
- Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questionsBlood, 2006
- Novel iron-specific fluorescent probesBioorganic & Medicinal Chemistry Letters, 2005
- Current issues with blood transfusions in sickle cell diseaseSeminars in Hematology, 2001
- Current issues with blood transfusions in sickle cell diseaseSeminars in Hematology, 2001
- Disorders of Iron MetabolismThe New England Journal of Medicine, 1999
- Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: orally active iron chelators with clinical potentialJournal of Medicinal Chemistry, 1993
- PREVENTION OF IRON LOADING IN TRANSFUSION-DEPENDENT THALASSÆMIAThe Lancet, 1978