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

Kento Sonoda; Saki Ujike; Akito Katayama; Norio Suzuki; Shin-Ichi Kawaguchi; Tadayuki Tsujita

doi:10.1016/j.bmc.2022.117039

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

Bioorg Med Chem. 2022 Nov 1:73:117039. doi: 10.1016/j.bmc.2022.117039. Epub 2022 Sep 29.

Authors

Kento Sonoda¹, Saki Ujike², Akito Katayama³, Norio Suzuki⁴, Shin-Ichi Kawaguchi⁵, Tadayuki Tsujita⁶

Affiliations

¹ Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan; Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, 1 Honjo-machi, Saga 840-8502, Japan; The United Graduate School of Agricultural Sciences, Kagoshima University, 1-21-24, Korimoto, Kagoshima 890-0065, Japan.
² Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan; Graduate School of Advanced Health Sciences, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan.
³ Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan.
⁴ Division of Oxygen Biology, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine; Applied Oxygen Physiology Project, New Industry Creation Hatchery Center (NICHe), Tohoku University, 2-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8575, Japan.
⁵ Center for Education and Research in Agricultural Innovation, Faculty of Agriculture, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan; The United Graduate School of Agricultural Sciences, Kagoshima University, 1-21-24, Korimoto, Kagoshima 890-0065, Japan; Graduate School of Advanced Health Sciences, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan. Electronic address: skawa@cc.saga-u.ac.jp.
⁶ Laboratory of Biochemistry, Department of Applied Biochemistry and Food Science, Faculty of Agriculture, Saga University, 1 Honjo-machi, Saga 840-8502, Japan; The United Graduate School of Agricultural Sciences, Kagoshima University, 1-21-24, Korimoto, Kagoshima 890-0065, Japan; Graduate School of Advanced Health Sciences, Saga University, 152-1 Shonan-cho, Karatsu, Saga 847-0021, Japan. Electronic address: tada@cc.saga-u.ac.jp.

PMID: 36198217
DOI: 10.1016/j.bmc.2022.117039

Abstract

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.

Keywords: 2-oxoglutarate; Hypoxia-inducible factor; Hypoxic stress; PHD inhibitors; Pyrazolidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Barbiturates
Humans
Hypoxia*
Hypoxia-Inducible Factor 1, alpha Subunit
Hypoxia-Inducible Factor-Proline Dioxygenases
Ketoglutaric Acids*

Substances

1,3-dimethylbarbituric acid
Barbiturates
Hypoxia-Inducible Factor 1, alpha Subunit
Hypoxia-Inducible Factor-Proline Dioxygenases
Ketoglutaric Acids
PyrzA compound