MK-8617-DataSheet-生命科學(xué)試劑-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEMK-8617Cat. No.: HY-101023CAS No.: 1187990-87-9分式: CHNO分量: 443.45作靶點(diǎn): HIF/HIF Prolyl-Hydroxylase作通路: Metabolic Enzyme/Protease儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 6 mg/mL (13.53

2、mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制備儲(chǔ)備液1 mM 2.2550 mL 11.2752 mL 22.5505 mL5 mM 0.4510 mL 2.2550 mL 4.5101 mL10 mM 0.2255 mL 1.1275 mL 2.2550 mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲(chǔ)備液，并請(qǐng)注意儲(chǔ)備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 MK-8617種低氧誘導(dǎo)因脯氨酰羥化酶 1-3 (HIF PHD1-3) 的服活性泛抑制劑，對(duì)于 PHD2 的 IC50 值

3、為1 nM。IC50 & Target IC50: 1 nM (PHD2) 1體外研究MK-8617 is an orally active pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) withan IC50 of 1 nM for PHD2. MK-8617 is not a significant inhibitor of the cytochrome p450 enzymes in vitro1/2 Master of Small Molecules 您邊的抑制劑師www.Me

4、dChemE(IC50), CYP1A2, 3A4, 2B6, 2C9, 2C19, or 2D6, 60 M, and is a moderate reversible inhibitor of CYP2C8 at1.6 M in vitro. The IC50 of MK-8617 is determined for factor inhibiting HIF (FIH) to be 18 M 1.體內(nèi)研究 Tritiated MK-8617 exhibits minimal metabolic turnover in liver microsomes from rat, dog, and

5、 monkey ( 1.PROTOCOLKinase Assay 1 The catalytic activity assays for the HIF-PHD isoforms are performed at subsaturating levels of 2-oxoglutarate. To each well of a 96-well plate are added 1 L of MK-8617 in DMSO and 20 L of assay buffercontaining 0.15 g/mL FLAG-tagged full length HIF-PHD isoform exp

6、ressed in and purified from baculovirus-infected Sf9 cells. After a 30 min preincubation at room temperature, the enzymatic reactions are initiated bythe addition of 4 L of substrates. After 2 h at room temperature, the reactions are terminated and signals aredeveloped by the addition of a 25 L quen

7、ch/detection mix to a final concentration of 1 mM ortho-phenanthroline, 0.1 mM EDTA, 0.5 nM anti-(His)6 LANCE reagent, 100 nM AF647-labeled streptavidin, and2 g/mL (His)6-VHL complex. The ratio of time-resolved fluorescence signals at 665 and 620 nm isdetermined, and percent inhibition is calculated

8、 relative to an uninhibited control sample run in parallel 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Male Sprague-Dawley rats (approximately 300 g each, n=15/arm) are dosed once daily for 28 days withAdministration 1 vehicle (25:75 v/v PE

9、G200/water+1 mol equiv of NaOH) or MK-8617 (1.5 or 15 mg/kg in vehicle). A group ofage-matched, untreated controls (n=15) are included in the experiment. On study days 3, 14, and 28, bloodsamples (0.25 mL) are obtained via jugular venipuncture and on study day 36 by cardiocentesis forhematological a

10、nd MK-8617 level analyses 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Debenham JS, et al. Discovery of N-Bis(4-methoxyphenyl)methyl-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), anOrally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1-3 (HIF PHD1-3) for the Treatment of Anemia. J Med Chem.2016 Dec 22;59(24):11039-11049.McePdfHeightCaution: Product has not been full