CN128: A New Orally Active Hydroxypyridinone Iron Chelator.,Journal of Medicinal Chemistry

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CN128: A New Orally Active Hydroxypyridinone Iron Chelator.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-02 , 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

Affiliation

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.

中文翻译：

CN128：一种新型的口服活性羟基吡啶酮铁螯合剂。

去铁胺，去铁酮和地拉罗司用于治疗全身性铁超负荷，尽管由于缺乏口服活性，疗效较低和副作用而存在局限性。这些限制导致寻找具有改善的治疗指数的口服活性铁螯合剂。去铁酮的功效较低是由于快速的葡萄糖醛酸化作用，导致形成非螯合的代谢产物。在这里，我们证明可以通过引入牺牲部位进行葡萄糖醛酸化来减少新陈代谢的影响。在对数P指导下对20个羟基吡啶并酮的研究导致CN128的鉴定。CN128的Fe（III）亲和力和金属选择性与去铁酮相似，log P值更具亲脂性，并且其铁清除能力优越。总体，

更新日期：2020-04-24

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