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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

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

Kenji Fukui, Yuichi Shinozaki, Hatsue Kobayashi, Katsuya Deai, Hiromi Yoshiuchi, Takuya Matsui, Akira Matsuo, Mutsuyoshi Matsushita, Tetsuhiro Tanaka, Masaomi Nangaku

Eur J Pharmacol. 2019 Sep 15;859:172532.

PMID: 31301309

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248695	Vascular Endothelial Growth Factor from mouse			Price

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