Improving lipophilicity of 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid increases its efficacy to activate hypoxia-inducible factors
Improving lipophilicity of 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid increases its efficacy to activate hypoxia-inducible factors
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DOI：
10.1016/j.bmc.2022.117039
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发表时间：
2022-10-02
影响因子：
3.5
通讯作者：
Tsujita，Tadayuki
中科院分区：
文献类型：
--
作者：
Sonoda，Kento;Ujike，Saki;Tsujita，Tadayuki
缺氧诱导因子（HIF）激活剂有助于治疗肾性贫血和缺血。最近，PyrzA（5-（1-乙酰基-5-苯基吡唑烷-3-亚基）-1，3-二甲基巴比妥酸），一种通过PHD抑制而不含2-酮戊二酸部分的HIF激活剂被报道。然而，PyrzA具有低亲脂性，并且有必要通过合成衍生物来改善其溶解性。在这项研究中，我们合成并评估了PyrzA的亲脂性更高的衍生物，发现与市售的HIF激活剂Roxadustat相比，它在低浓度下表现出更高的HIF活性和稳定能力。
Hypoxia-inducible factor (HIF) activators aid the treatment of renal anemia and ischemia. Recently, PyrzA (5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid), a HIF activator by PHD inhibition without a 2-oxoglutarate moiety was reported. However, PyrzA has low lipophilicity, and it was necessary to improve its solubility by synthesizing derivatives. In this study, we synthesized and evaluated a higher lipophilic derivative of PyrzA and found that it exhibited higher HIF activity and stabilizing ability at low concentrations compared to Roxadustat, a commercially available HIF activator.