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CN128: A New Orally Active Hydroxypyridinone Iron Chelator
- Source :
- Journal of Medicinal Chemistry. 63:4215-4226
- Publication Year :
- 2020
- Publisher :
- American Chemical Society (ACS), 2020.
-
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 nonchelating metabolite. Here, we demonstrate that the influence of metabolism can be reduced by introducing a sacrificial site for glucuronidation. A log P-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 log P 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.
- Subjects :
- Drug
Iron Overload
Pyridones
media_common.quotation_subject
Metabolite
Guinea Pigs
Glucuronidation
Administration, Oral
Pharmacology
Iron Chelating Agents
01 natural sciences
Rats, Sprague-Dawley
Mice
03 medical and health sciences
chemistry.chemical_compound
Therapeutic index
Drug Discovery
medicine
Animals
Humans
Tissue Distribution
030304 developmental biology
media_common
0303 health sciences
Dose-Response Relationship, Drug
Chemistry
Deferasirox
Rats
0104 chemical sciences
Deferoxamine
010404 medicinal & biomolecular chemistry
Toxicity
Molecular Medicine
Deferiprone
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 63
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....e10e2dec69b1e986df0d275bb83f3970