Improving lipophilicity of 5-(1-acetyl-5-phenylpyrazolidin-3-ylidene)-1,3-dimethylbarbituric acid increases its efficacy to activate hypoxia-inducible factors.

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.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.U. is a chief operation officer, and S-i.K. and T.T. are advisory members for Tetra Create Co., Ltd. All other authors declare no conflicts of interest. Compounds 1a and 9c are available from Tetra Create Co., Ltd.
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