Synonym
TP0463518; TP-0463518; TP 0463518;
IUPAC/Chemical Name
(1-((6-(4-chlorophenoxy)pyridin-3-yl)methyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonyl)glycine
InChi Key
HMMHKGLPKAQOOH-UHFFFAOYSA-N
InChi Code
InChI=1S/C20H18ClN3O6/c21-13-2-4-14(5-3-13)30-16-6-1-12(9-22-16)11-24-8-7-15(25)18(20(24)29)19(28)23-10-17(26)27/h1-6,9,25H,7-8,10-11H2,(H,23,28)(H,26,27)
SMILES Code
O=C(O)CNC(C1=C(O)CCN(CC2=CC=C(OC3=CC=C(Cl)C=C3)N=C2)C1=O)=O
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
The correlation factors for serum EPO and the serum TP0463518 levels were 0.95 in mice and 0.92 in rats. TP0463518 also increased the serum EPO level in 5/6 nephrectomized chronic kidney disease model rats at a dose of 10 mg/kg, with a correlation factor for serum EPO and the serum TP0463518 levels of 0.82. Finally, the effect of TP0463518 in monkeys was investigated. TP0463518 was promptly removed with a half-life of 5.2 h and increased the area under the curve (AUC) of EPO at a dose of 5 mg/kg. The EPO and TP0463518 levels were also correlated. P0463518 induces endogenous EPO with a strong pharmacokinetic-pharmacodynamic correlation and may contribute to desirable hemoglobin control in patients with renal anemia.
Biological target:
TP0463518 is a potent hypoxia-inducible factor prolyl hydroxylases (PHDs) inhibitor with a Ki value of 5.3 nM for human PHD2.
In vitro activity:
To examine whether TP0463518 exerts EPO-producing effect in the liver cells, we addressed the effect of TP0463518 on EPO mRNA expression and EPO secretion in the human and rat liver cell lines, HepG2 and H4-II-E-C3. After the treatment of the cells with TP0463518 for 24 hours, EPO mRNA levels in both HepG2 and H4-II-E-C3 cells increased at 10 μM or more; the increase at 30 μM was 4.04- and 3.47-fold higher than control group, respectively (Fig. 8, A and B). EPO concentration in the medium of HepG2 cells treated with TP0463518 for 72 hours increased from 38.7 mU/ml in control wells to 74.0 mU/ml at 30 μM (Fig. 8C). EPO concentration in medium of H4-II-E-C3 cells treated with TP0463518 for 72 hours also increased from 79.1 pg/ml in control wells to 254.9 pg/ml at 30 μM (Fig. 8D). These results indicated that TP0463518 increased EPO expression not only in rat liver but also in human liver.
Reference: J Pharmacol Exp Ther. 2019 Dec;371(3):675-683. https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=31585986
In vivo activity:
The effect of TP0463518 in inducing EPO production in the kidney and liver was examined by measuring the hypoxia-inducible factor 2α (HIF-2α), EPO mRNA, and serum EPO levels in normal and bilaterally nephrectomized rats. Furthermore, whether liver-derived EPO improved anemia was investigated in 5/6 nephrectomized (5/6 Nx) rats. TP0463518 scarcely increased the HIF-2α and EPO mRNA expression levels in the kidney cortex, whereas oral administration of TP0463518 at 40 mg/kg dramatically increased the HIF-2α 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-HIF2α-EPO pathway in erythropoiesis, but a new therapeutic alternative for renal anemia.
Reference: J Pharmacol Exp Ther. 2019 Dec;371(3):675-683. https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=31585986
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
40.0 |
92.63 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
431.83
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
In vitro protocol:
1. Kato S, Ochiai N, Takano H, Io F, Takayama N, Koretsune H, Kunioka EI, Uchida S, Yamamoto K. TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver. J Pharmacol Exp Ther. 2019 Dec;371(3):675-683. doi: 10.1124/jpet.119.258731. Epub 2019 Oct 4. PMID: 31585986.
In vivo protocol:
1. Kato S, Takayama N, Takano H, Koretsune H, Koizumi C, Kunioka EI, Uchida S, Takahashi T, Yamamoto K. TP0463518, a novel inhibitor for hypoxia-inducible factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with a good pharmacokinetics-pharmacodynamics correlation. Eur J Pharmacol. 2018 Nov 5;838:138-144. doi: 10.1016/j.ejphar.2018.08.044. Epub 2018 Sep 1. PMID: 30179610.
2. Kato S, Ochiai N, Takano H, Io F, Takayama N, Koretsune H, Kunioka EI, Uchida S, Yamamoto K. TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver. J Pharmacol Exp Ther. 2019 Dec;371(3):675-683. doi: 10.1124/jpet.119.258731. Epub 2019 Oct 4. PMID: 31585986.
1: Kato S, Takayama N, Takano H, Koretsune H, Koizumi C, Kunioka EI, Uchida S,
Takahashi T, Yamamoto K. TP0463518, a novel inhibitor for hypoxia-inducible
factor prolyl hydroxylases, increases erythropoietin in rodents and monkeys with
a good pharmacokinetics-pharmacodynamics correlation. Eur J Pharmacol. 2018 Nov
5;838:138-144. doi: 10.1016/j.ejphar.2018.08.044. Epub 2018 Sep 1. PubMed PMID:
30179610.
2: Shinfuku A, Shimazaki T, Fujiwara M, Sato F, Watase H, Numazaki T, Kawakita Y,
Mutoh M, Yamasaki H, Takayama N, Kato S, Sugimoto T, Maruyama J. Novel Compound
Induces Erythropoietin Secretion through Liver Effects in Chronic Kidney Disease
Patients and Healthy Volunteers. Am J Nephrol. 2018;48(3):157-164. doi:
10.1159/000492181. Epub 2018 Sep 3. PubMed PMID: 30176654; PubMed Central PMCID:
PMC6214603.
