TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver.

Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver. The 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518) is a novel PHD 1/2/3 pan inhibitor; however, the main source of EPO production after TP0463518 administration remained to be investigated. We examined the effect of TP0463518 in inducing EPO production in the kidney and liver by measuring the hypoxia-inducible factor 2 (HIF-2), EPO mRNA, and serum EPO levels in normal and bilaterally nephrectomized rats. Furthermore, we examined whether liver-derived EPO improved anemia in 5/6 nephrectomized (5/6 Nx) rats. TP0463518 scarcely increased the HIF-2 and EPO mRNA expression levels in the kidney cortex, whereas oral administration of TP0463518 at 40 mg/kg dramatically increased the HIF-2 level from 0.27 to 1.53 fmol/mg and the EPO mRNA expression level by 1300-fold in the livers of healthy rats. After administration of TP0463518 at 20 mg/kg, the total EPO mRNA expression level in the whole liver was 22-fold that in the whole kidney. In bilaterally nephrectomized rats, TP0463518 raised the serum EPO concentration from 0 to 180 pg/ml at 20 mg/kg. Furthermore, repeated administration of TP0463518 at 10 mg/kg increased the reticulocyte count in 5/6 Nx rats on day 7 and raised the hemoglobin level on day 14. The present study revealed that TP0463518 specifically induced EPO production in the liver and improved anemia. The characteristic feature of TP0463518 would lead to not only a more detailed understanding of the PHD-HIF2-EPO pathway in erythropoiesis, but a new therapeutic alternative for renal anemia. SIGNIFICANCE STATEMENT: Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver; however, their effects on renal EPO production have been shown to vary depending on the experimental conditions. The authors found that 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518), a PHD 1/2/3 pan inhibitor, specifically induced EPO production in the liver and that the liver-derived EPO was pharmacologically effective. Investigation of the effects of TP0463518 may pave the way for the development of a new therapeutic alternative for renal anemia patients.