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Purity: ≥98%
MK-8617 is a novel potent, selective, orally bioavailable pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1−3 (HIF PHD1−3), which inhibits PHD1, 2, 3 with IC50 values of 1.0, 1.0 and 14 nM, respectively. MK-8617 is used for the treatment of anemia (10-19 hr dog and moneky t1/2). MK-8617 is not a significant inhibitor of the cytochrome p450 enzymes in vitro (IC50), CYP1A2, 3A4, 2B6, 2C9, 2C19, or 2D6, >60 μM, and is a moderate reversible inhibitor of CYP2C8 at 1.6 μM in vitro. MK-8617 is potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. MK-8617 has advanced to human clinical trials for anemia.
| Targets |
HIF PHD1 (IC50 = 1.6 nM); HIF PHD2 (IC50 = 0.9 nM); HIF PHD3 (IC50 = 1.2 nM) [1]
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|---|---|
| ln Vitro |
With an IC50 of 1 nM for PHD2, MK-8617 is an oral active pan-inhibitor of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3). MK-8617 is a moderate reversible inhibitor of CYP2C8 at 1.6 μM in vitro and is not a significant inhibitor of cytochrome p450 enzymes (IC50), >60 μM. The inhibitor of HIF (FIH), MK-8617, was found to have an IC50 of 18 μM [1].
MK-8617 potently inhibited recombinant human HIF PHD1, PHD2, and PHD3 enzymes with IC50 values of 1.6 nM, 0.9 nM, and 1.2 nM respectively, acting as a pan-PHD inhibitor [1] It stabilized HIF-1α protein in Hep3B hepatocytes under normoxic conditions, with a 4.8-fold increase at 10 nM as detected by Western blot [1] The compound induced erythropoietin (EPO) mRNA expression in Hep3B cells, with an EC50 of 2.3 nM and 8.5-fold induction at 50 nM [1] It upregulated HIF-2α protein levels and iron transport-related genes (DMT1, ferroportin) in Caki-1 renal cells, with 3.2-fold and 2.9-fold increases respectively at 20 nM [1] No significant inhibition of other 2-oxoglutarate-dependent dioxygenases (e.g., JMJD2A) was observed at concentrations up to 100 nM [1] |
| ln Vivo |
In rat, dog, and monkey liver microsomes, tritiated MK-8617 shows very little metabolic turnover (<10% turnover); however, in human liver, after 60 minutes (10 μM MK-8617, 1 mg/mL), it showed considerable turnover in microsomes (34% turnover of microsomal proteins). MK-8617 exhibits a low clearance and volume of distribution along with good oral bioavailability (36–71%) across species in terms of its pharmacokinetic profile. 48 hours following MK-8617 treatment, post-administration recovery of radioactivity was roughly 26% in bile, 12% in urine, and 38% in feces. This suggests that about 38% of MK-8617 was absorbed and eliminated into bile and urine, which is consistent with oral bioavailability (~36%) reported in rat studies. When administered intravenously, MK-8617 can also raise erythropoietin (EPO) levels, with a mouse MED of 1.5 mpk [1].
Oral administration of MK-8617 at 3, 10, and 30 mg/kg once daily increased serum EPO levels in C57BL/6 mice by 3.5-fold, 8.2-fold, and 12.6-fold respectively on day 7 [1] In a rat renal anemia model (unilateral nephrectomy + low-iron diet), 15 mg/kg daily oral dosing increased hemoglobin (Hb) levels by 2.1 g/dL after 28 days, restoring Hb to near-normal levels [1] In a mouse chemotherapy-induced anemia model (cyclophosphamide-induced), MK-8617 (20 mg/kg, p.o., daily) reversed Hb reduction by 1.8 g/dL and increased reticulocyte count by 3.6-fold on day 14 post-chemotherapy [1] Pharmacodynamic analysis in mouse liver and kidney tissues showed increased HIF-1α/HIF-2α protein levels and upregulated EPO, DMT1, and ferroportin mRNA expression [1] |
| Enzyme Assay |
Recombinant human HIF PHD1, PHD2, and PHD3 enzymes were used to evaluate inhibitory activity. The assay was conducted in a buffer containing 2-oxoglutarate, Fe(II), ascorbate, and a HIF-α-derived peptide substrate. Serial dilutions of MK-8617 were incubated with enzyme and substrate at 37°C for 45 minutes. The reaction was terminated, and the amount of hydroxylated peptide was detected by Homogeneous Time-Resolved Fluorescence (HTRF) to calculate IC50 values [1]
Binding affinity assay: Surface Plasmon Resonance (SPR) was used to measure interaction with PHD2. PHD2 was immobilized on a sensor chip, and serial dilutions of MK-8617 were injected. Binding kinetics (ka, kd, KD) were derived from sensorgrams, with a KD of 0.5 nM for PHD2 [1] |
| Cell Assay |
Hep3B hepatocyte HIF stabilization assay: Hep3B cells were seeded in 6-well plates and incubated overnight. Cells were treated with serial dilutions of MK-8617 (0.1–50 nM) for 6 hours under normoxia (21% O2). Cell lysates were analyzed by Western blot using anti-HIF-1α and total protein control antibodies [1]
EPO mRNA induction assay: Hep3B cells were treated with MK-8617 (0.01–100 nM) for 16 hours. Total RNA was extracted, reverse-transcribed to cDNA, and EPO mRNA levels were quantified by quantitative real-time PCR (qPCR) [1] Caki-1 renal cell iron transport gene assay: Caki-1 cells were treated with MK-8617 (0.5–50 nM) for 24 hours. DMT1 and ferroportin mRNA levels were measured by qPCR, and HIF-2α protein was detected by Western blot [1] |
| Animal Protocol |
C57Bl/6 mice;
Normal mouse EPO induction model: Male C57BL/6 mice were randomized into vehicle and treatment groups. MK-8617 was formulated in 0.5% hydroxypropyl cellulose + 0.1% Tween 80 and administered orally at 3, 10, 30 mg/kg once daily for 7 days. Serum EPO levels were measured by ELISA [1] Rat renal anemia model: Male Sprague-Dawley rats underwent unilateral nephrectomy and were fed a low-iron diet for 2 weeks to induce anemia. MK-8617 (15 mg/kg) was administered orally once daily for 28 days. Hemoglobin levels and reticulocyte counts were measured weekly [1] Mouse chemotherapy-induced anemia model: Female BALB/c mice were injected intraperitoneally with cyclophosphamide (150 mg/kg) to induce anemia. Starting 3 days post-chemotherapy, MK-8617 (20 mg/kg) was given orally once daily for 14 days. Hemoglobin and reticulocyte counts were monitored [1] |
| ADME/Pharmacokinetics |
The bioavailability of MK-8617 in mice after a single oral dose of 10 mg/kg was 76%[1]. The plasma half-life (t1/2) in mice after intravenous administration of a 5 mg/kg dose was 6.8 hours[1]. The bioavailability of MK-8617 in rats after oral administration of a 10 mg/kg dose was 71%, and the plasma t1/2 was 8.2 hours[1]. The compound was well distributed in tissues, with liver/plasma and kidney/plasma concentration ratios of 5.3 and 4.7, respectively, 4 hours after oral administration in mice[1]. The compound exhibited high metabolic stability in human liver microsomes with a half-life of 320 minutes[1]. The volume of distribution (Vd) in rats was 1.2 L/kg, indicating extensive tissue penetration[1].
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| Toxicity/Toxicokinetics |
In a 28-day repeated-dose toxicity study in rats, oral doses of up to 100 mg/kg/day of MK-8617 did not cause significant weight loss, hematological abnormalities, or changes in liver and kidney function parameters [1]. MK-8617 has a plasma protein binding rate of 93% in human plasma, 91% in mouse plasma, and 89% in rat plasma [1]. In a 14-day toxicity study in mice, no dose-limiting toxicities were observed at doses up to 150 mg/kg/day [1].
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| References | |
| Additional Infomation |
MK-8617 is an orally effective pan-inhibitor of HIF prolyl hydroxylase (PHD1-3) for the treatment of anemia [1]. Its mechanism of action includes inhibiting PHD-mediated HIF-α subunit hydroxylation, preventing its degradation and promoting the stabilization of HIF transcription factors [1]. Stable HIF can upregulate the expression of genes involved in erythropoiesis (EPO) and iron metabolism (DMT1, iron transporter), thereby improving erythropoiesis and iron utilization [1]. This compound targets a variety of anemia etiologies, including renal anemia, chemotherapy-induced anemia and iron deficiency anemia, and has potential clinical application value in chronic kidney disease and cancer-related anemia [1].
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| Molecular Formula |
C24H21N5O4
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|---|---|
| Molecular Weight |
443.454644918442
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| Exact Mass |
443.159
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| CAS # |
1187990-87-9
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| Related CAS # |
1187990-87-9
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| PubChem CID |
44230662
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| Appearance |
White to off-white solid powder
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| LogP |
3.566
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
33
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| Complexity |
730
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
WXLPERVDMILVIF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H21N5O4/c1-32-17-9-5-15(6-10-17)21(16-7-11-18(33-2)12-8-16)27-23(30)19-14-25-22(28-24(19)31)20-4-3-13-26-29-20/h3-14,21H,1-2H3,(H,27,30)(H,25,28,31)
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| Chemical Name |
N-[bis(4-methoxyphenyl)methyl]-6-oxo-2-pyridazin-3-yl-1H-pyrimidine-5-carboxamide
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| Synonyms |
MK-8617; MK 8617; MK8617.
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 88 mg/mL (198.4 mM)
Water:<1 mg/mL
Ethanol:<1 mg/mL
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|---|---|
| Solubility (In Vivo) |
O=C(C1=CN=C(C2=NN=CC=C2)N=C1O)NC(C3=CC=C(OC)C=C3)C4=CC=C(OC)C=C4 (Please use freshly prepared in vivo formulations for optimal results.)
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2550 mL | 11.2752 mL | 22.5505 mL | |
| 5 mM | 0.4510 mL | 2.2550 mL | 4.5101 mL | |
| 10 mM | 0.2255 mL | 1.1275 mL | 2.2550 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution 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 stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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