JTZ-951 (enarodustat), a hypoxia-inducibe factor prolyl hydroxylase inhibitor, stabilizes HIF-α protein and induces erythropoiesis without effects on the function of vascular endothelial growth factor.

Abstract

JTZ-951 (enarodustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor. JTZ-951 has inhibitory activities on human HIF-prolyl hydroxylase 1-3, but not on various receptors or enzymes. In Hep3B cells, JTZ-951 increased HIF-1α and HIF-2α protein levels, erythropoietin (EPO) mRNA levels, and EPO production. In normal rats, after a single oral dose of JTZ-951, the hepatic and renal EPO mRNA levels and plasma EPO concentrations were also increased. In 5/6-nephrectomized rats, repeated oral doses of JTZ-951 once daily or intermittent dosing showed the erythropoiesis stimulating effect. The administration of JTZ-951 at a high dose increased plasma vascular endothelial growth factor (VEGF) levels; however, retinal VEGF mRNA levels and the retinal vascular permeability were not changed. Finally, we evaluated the effect of JTZ-951 in a colorectal cancer cell-inoculated mouse model. Although JTZ-951 at a high dose increased the plasma VEGF, it had no effect on tumor growth. In summary, JTZ-951 induces erythropoiesis without affecting VEGF function. Therefore, it is expected that JTZ-951 will be a new oral candidate that increases and maintains hemoglobin concentrations in renal anemia patients.

• Authors: Kenji Fukui, Yuichi Shinozaki, Hatsue Kobayashi, Katsuya Deai, Hiromi Yoshiuchi, Takuya Matsui, Akira Matsuo, Mutsuyoshi Matsushita, Tetsuhiro Tanaka, Masaomi Nangaku
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 859 Pg. 172532 (Sep 15 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 31301309 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• N-substituted Glycines
• Prolyl-Hydroxylase Inhibitors
• Pyridines
• RNA, Messenger
• Triazoles
• Vascular Endothelial Growth Factor A
• Erythropoietin
• endothelial PAS domain-containing protein 1
• Hypoxia-Inducible Factor-Proline Dioxygenases
• enarodustat

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cell Line
• Dose-Response Relationship, Drug
• Erythropoiesis (drug effects)
• Erythropoietin (genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases (antagonists & inhibitors)
• N-substituted Glycines (pharmacology)
• Prolyl-Hydroxylase Inhibitors (pharmacology)
• Protein Stability (drug effects)
• Pyridines (pharmacology)
• RNA, Messenger (genetics)
• Rats
• Rats, Sprague-Dawley
• Triazoles (pharmacology)
• Vascular Endothelial Growth Factor A (biosynthesis, genetics, metabolism)