TY - JOUR
T1 - CN128
T2 - A New Orally Active Hydroxypyridinone Iron Chelator
AU - Chen, Wenteng
AU - Yuan, Xin
AU - Li, Zhi
AU - Lu, Zidong
AU - Kong, Sisi
AU - Jiang, Huidi
AU - Du, Houbing
AU - Pan, Xiuhong
AU - Nandi, Manasi
AU - Kong, Xiaole
AU - Brown, Kathryn
AU - Liu, Zudong
AU - Zhang, Guolin
AU - Hider, Robert C.
AU - Yu, Yongping
PY - 2020/4/23
Y1 - 2020/4/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85084025883&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.0c00137
DO - 10.1021/acs.jmedchem.0c00137
M3 - Article
C2 - 32208614
AN - SCOPUS:85084025883
SN - 0022-2623
VL - 63
SP - 4215
EP - 4226
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -