2. Academic Validation
  3. CN128: A New Orally Active Hydroxypyridinone Iron Chelator

CN128: A New Orally Active Hydroxypyridinone Iron Chelator

  • J Med Chem. 2020 Apr 23;63(8):4215-4226. doi: 10.1021/acs.jmedchem.0c00137.
Wenteng Chen 1,  Xin Yuan 2,  Zhi Li 1,  Zidong Lu 3,  Sisi Kong 1,  Huidi Jiang 1,  Houbing Du 4,  Xiuhong Pan 4,  Manasi Nandi 3,  Xiaole Kong 3,  Kathryn Brown 3,  Zudong Liu 2,  Guolin Zhang 1,  Robert C Hider 3,  Yongping Yu 1
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China.
  • 2 Hangzhou Zede Pharma-Tech Co. Ltd., Hangzhou 311121, Zhejiang Province, China.
  • 3 Institute of Pharmaceutical Science, Franklin-Wilkins Building, King's College London, 150 Stamford Street, SE1 9NH London, UK.
  • 4 Suzhou Xishan Zhongke Drug R&D Co. Ltd., Suzhou 215104, Jiangsu Province, China.
PMID: 32208614 DOI: 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 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.

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