CN128: A New Orally Active Hydroxypyridinone Iron Chelator

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.