MK-8617 |
Catalog No.GC19251
One-Click Copy Product Info
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MK-8617 is an orally active pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) with an IC50 of 1 nM for PHD2.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1187990-87-9
Sample solution is provided at 25 µL, 10mM.
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MK-8617 is an orally active pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) with an IC50 of 1 nM for PHD2.
MK-8617 is an orally active pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) with an IC50 of 1 nM for PHD2. MK-8617 is not a significant inhibitor of the cytochrome p450 enzymes in vitro (IC50), CYP1A2, 3A4, 2B6, 2C9, 2C19, or 2D6, >60 uM, and is a moderate reversible inhibitor of CYP2C8 at 1.6 uM in vitro. The IC50 of MK-8617 is determined for factor inhibiting HIF (FIH) to be 18 uM[1].
Tritiated MK-8617 exhibits minimal metabolic turnover in liver microsomes from rat, dog, and monkey (<10% turover) but significant turnover in human liver microsomes (34% turnover) after 60 min (10 uM MK-8617, 1 mg/mL microsomal protein). In terms of its pharmacokinetic profile, MK-8617 shows good oral bioavailability across species (36 to 71%), with low clearance and volume of distribution. After 48 h treatment of MK-8617, postdose recovery of the radioactivity is about 26% bile, 12% urine, and 38% in feces, indicating that ~38% of the MK-8617 is absorbed and eliminated into bile and urine which is consistent with the oral bioavailability (~36%) observed in the rat study. MK-8617 also elicits an increase in erythropoietin (EPO) levels with a mouse MED of 1.5 mpk when dosed iv[1].
References:
[1]. Debenham JS, et al. Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally 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.
Kinase experiment: | 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 μL of MK-8617 in DMSO and 20 μL of assay buffer containing 0.15 μg/mL FLAG-tagged full length HIF-PHD isoform expressed in and purified from baculovirus-infected Sf9 cells. After a 30 min preincubation at room temperature, the enzymatic reactions are initiated by the addition of 4 μL of substrates. After 2 h at room temperature, the reactions are terminated and signals are developed by the addition of a 25 μL quench/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, and 2 μg/mL (His)6-VHL complex. The ratio of time-resolved fluorescence signals at 665 and 620 nm is determined, and percent inhibition is calculated relative to an uninhibited control sample run in parallel[1]. |
Animal experiment: | Male Sprague-Dawley rats (approximately 300 g each, n=15/arm) are dosed once daily for 28 days with vehicle (25:75 v/v PEG200/water+1 mol equiv of NaOH) or MK-8617 (1.5 or 15 mg/kg in vehicle). A group of age-matched, untreated controls (n=15) are included in the experiment. On study days 3, 14, and 28, blood samples (~0.25 mL) are obtained via jugular venipuncture and on study day 36 by cardiocentesis for hematological and MK-8617 level analyses[1]. |
References: [1]. Debenham JS, et al. Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally 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. | |
| Cas No. | 1187990-87-9 | SDF | |
| Canonical SMILES | O=C(C1=CN=C(C2=NN=CC=C2)N=C1O)NC(C3=CC=C(OC)C=C3)C4=CC=C(OC)C=C4 | ||
| Formula | C24H21N5O4 | M.Wt | 443.45 |
| Solubility | DMSO : 6 mg/mL (13.53 mM) | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.255 mL | 11.2752 mL | 22.5505 mL |
| 5 mM | 451 μL | 2.255 mL | 4.5101 mL |
| 10 mM | 225.5 μL | 1.1275 mL | 2.255 mL |
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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL saline, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
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- Purity: >98.00% Appearance: A solid
- COA (Certificate of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 16 reference(s) in Google Scholar.)