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TP0463518

Catalog No. T5392   CAS 1558021-37-6

TP-0463518 is a highly potent HIF prolyl hydroxylase (PHD) inhibitor (IC50s: 13 nM and 18 nM for human and rat PHD2, respectively).

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TP0463518 Chemical Structure
TP0463518, CAS 1558021-37-6
Pack Size Availability Price/USD Quantity
5 mg In stock $ 47.00
10 mg In stock $ 72.00
25 mg In stock $ 122.00
50 mg In stock $ 198.00
100 mg In stock $ 372.00
1 mL * 10 mM (in DMSO) In stock $ 52.00
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Purity: 99.43%
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Biological Description
Chemical Properties
Storage & Solubility Information
Description TP-0463518 is a highly potent HIF prolyl hydroxylase (PHD) inhibitor (IC50s: 13 nM and 18 nM for human and rat PHD2, respectively).
Targets&IC50 PHD3 (human):63 nM (cell free), PHD2 (rat):18 nM (cell free), PHD2 (human):13 nM (cell free), PHD1 (human):18 nM (cell free)
In vitro TP0463518 competitively inhibited human PHD2 with a Ki value of 5.3?nM. TP0463518 also inhibited human PHD1/3 with IC50 values of 18 and 63?nM as well as monkey PHD2 with an IC50 value of 22?nM.
In vivo In normal mice and rats, TP0463518 significantly increased the serum EPO levels at doses of 5 and 20?mg/kg, respectively. 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. 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.
Kinase Assay The PHDs inhibition studies were performed using fluorescence polarization.FITC-HIF and 2-oxoglutarate were mixed with enzyme solution in a reaction buffer (20 mM Tris-HCl [pH 7.5],5 mM KCl,1.5 mM MgCl2,10 μM FeSO4,2 mM ascorbic acid,1 mM DTT) with or without various concentrations of TP0463518.The concentrations of FITC-HIF and 2-oxoglutarate were twice the Km values of each enzyme.The reaction temperature was 30?C,and the reaction time was optimized to each PHD enzyme to obtain the initial velocity (9 to 20 min).At the end of the reaction,a stop solution containing 20 mM of EDTA and anti-hydroxylated HIF antibody was added to the reaction buffer.Then,the fluorescence (ex: 480 nm,em: 535 nm) was measured using EnVision to calculate the millipolarization (mP) value.The mP values and the corresponding hydroxylated HIF concentration were proportional,so we used the mP values as the activities.The IC50 values were calculated using SAS version 9.2 using a nonlinear least-squares method.To determine the mode of inhibition,the activity of PHD2 was measured with various concentrations of 2-oxoglutarate (0.025 to 8 μM) and TP0463518 (0 to 40 μM).Then the apparent Vmax and Km corresponding to each TP0463518 concentration were compared.The mode of inhibition was confirmed using a double reciprocal plot.
Animal Research Nine-week-old Balb/c mice were randomly assigned to a vehicle or a 5 to 40 mg/kg dose of TP0463518 group. The mice were orally treated with 0.5% methylcellulose or a TP0463518 dosing suspension. Blood was collected at 6 h after administration from the orbital plexus under deep anesthesia, and euthanasia was performed without awakening. An aliquot of blood was mixed with EDTA, and the remaining blood sample was left to stand at room temperature for 15 min. The samples were then centrifuged (2130 x g for 10 min at 4°C) to prepare the plasma and serum.
Molecular Weight 431.83
Formula C20H18ClN3O6
CAS No. 1558021-37-6

Storage

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

Solubility Information

DMSO: 110 mg/mL (254.73 mM)

TargetMolReferences and Literature

1. Kato S, et al. 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.

Related compound libraries

This product is contained In the following compound libraries:
Bioactive Compounds Library Max Glutamine Metabolism Compound Library Metabolism Compound Library Epigenetics Compound Library Inhibitor Library Anti-Metabolism Disease Compound Library Transcription Factor-Targeted Compound Library HIF-1 Signaling Pathway Compound Library Anti-Pancreatic Cancer Compound Library Anti-COVID-19 Compound Library

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Keywords

TP0463518 1558021-37-6 Chromatin/Epigenetic Metabolism HIF/HIF Prolyl-Hydroxylase HIF-PH TP-0463518 HIFs TP 0463518 inhibit Inhibitor Hypoxia-inducible factors inhibitor

 

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