Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 73, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2022.117039
Keywords
PHD inhibitors; 2-oxoglutarate; Hypoxic stress; Pyrazolidine; Hypoxia-inducible factor
Funding
- JSPS KAKENHI [19H04057, 22K19755, 19K17746]
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In this study, a higher lipophilic derivative of PyrzA was synthesized and evaluated, showing higher HIF activity and stabilizing ability at low concentrations compared to the commercially available HIF activator Roxadustat.
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.
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