化合物TP0463518 T5392

Product Introduction
Bioactivity


英文名: TP0463518

描述: TP0463518 是缺氧诱导因子脯氨酰羟化酶抑制剂，能够作用于人 PHD2(Ki= 5.3 nM)。它还抑制人PHD1/PHD3，IC50分别为 18 和 63 nM，以及猴 PHD2(IC50=22 nM)。

激酶实验: 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.

动物实验: 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.

体外活性: TP0463518 竞争性抑制人类 PHD2，Ki 值为 5.3nM。此外，TP0463518 也对人类 PHD1/3 表现出抑制作用，IC50 值分别为 18 nM 和 63 nM，以及对猴子 PHD2 的抑制作用，IC50 值为 22nM。

体内活性: 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.

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

溶解度: DMSO : 110 mg/mL (254.73 mM)


关键字: TP0463518 | HIF-PH | TP-0463518 | HIFs | TP 0463518 | inhibit | Inhibitor | HIF/HIF Prolyl-Hydroxylase | Hypoxia-inducible factors

相关产品: Fraxinellone | JNJ-42041935 | FG-2216 | Oroxylin A | Notoginsenoside Ft1 | Albendazole | PHD-IN-2 | Chloramphenicol | HIF-1 alpha (556-574) (TFA) | PT-2385

相关库: Anti-Cancer Metabolism Compound Library | Transcription Factor-Targeted Compound Library | Anti-Cancer Compound Library | Bioactive Compounds Library Max | Anti-Metabolism Disease Compound Library | Inhibitor Library | Epigenetics Compound Library | Anti-Pancreatic Cancer Compound Library | NO PAINS Compound Library | Glycolysis Compound Library

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