| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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Purity: ≥98%
Mitapivat (previously PKM2 activator 1020; AG-348; PKR-IN-1; trade name Pyrukynd) is a PKM2 activator (pyruvate kinase activator) that has potential use for the treatment of pyruvate kinase deficiency. As of Feb 2022, Mitapivat has been approved for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. Mitapivat is a potent human R-type pyruvate kinase (PKR) inhibitor that also shows potency for mutant PKR including R510Q PKR, R532W PKR, T384W PKR etc. Pyruvate kinase type M2, which is expressed in multiple tumor cell types and plays a key role in aerobic glycolysis, has nonglycolytic functions and can regulate transcription and cell proliferation. Thus it has been reported that small molecule activators of pyruvate kinase isozyme M2 (PKM2) may suppress tumor formation but have an unknown effect on established tumors.
| ln Vitro |
In healthy donor erythrocytes, mitapivat (0.1 nM-100 μM; 16 h) activates WT PK-R[1]. In red blood cells, mitapivat (0.01 nM-10 μM; 16 h) stimulates ATP generation in a dose-dependent way [1].
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| ln Vivo |
In a mouse model of beta-thalassemia, mitapivat (50 mg/kg; oral; twice daily for 21 days) improves anemia [2].
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: RBC cells Tested Concentrations: 0.1 nM-100 µM Incubation Duration: 16 h (incubate overnight) Experimental Results: Increased PK-R activity in a dose-dependent manner to ~2.5-fold of DMSO control with an AC50 of 62 nM. Cell Viability Assay[1] Cell Types: RBC cells Tested Concentrations: 0.01 nM-10 µM Incubation Duration: 16 h (incubate overnight) Experimental Results: Consistently increased ATP levels in a dose-dependent manner by an average of 60% over DMSO control with an AC50 of 10.9 nM. |
| Animal Protocol |
Animal/Disease Models: WT C57B6 and Hbbth3/+ mice (both are 2-month-old female mice; β-thalassemia model)[2].
Doses: 50 mg/kg Route of Administration: In animal feedings; single daily for 3 weeks. Experimental Results: Increased the expression of pyruvate kinase isoforms in both red cells and erythroid precursors from Hbbth3/+ mice. Elevated pyruvate kinase activity in cells from Hbbth3/+ mice, and markedly increased ROS level in erythrocytes. Increased the expression of PKM2 in polychromatic and orthochromatic erythroblasts of Hbbth3/+ mice. Animal/Disease Models: WT C57B6 and Hbbth3/+ mice (both are 2-month-old female mice; β-thalassemia model)[2]. Doses: 50 mg/kg Route of Administration: po (oral gavage), twice (two times) daily for 21 days. Experimental Results: Ameliorated ineffective erythropoiesis and anemia in Hbbth3/+ mice and increased ATP, decreased ROS production, as well as decreased markers of mitochondrial dysfunction associated with improved mitochondrial clearance. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
The absolute bioavailability of mitapivat after a single dose is approximately 73%. Mitapivat exposure increases dose-proportionally. Following twice-daily oral administration of mitapivat at the dose of 5 mg, 20 mg, and 50 mg, the mean (CV%) Cmax at steady state were 101.2 (17%) ng/mL, 389.9 (18%) ng/mL, and 935.2 (18%) ng/mL, respectively. The mean (CV%) AUC were 450.4 (28%) ng x h/mL, 1623.8 (28%) ng x h/mL, and 3591.4 (28%) ng x h/mL, respectively. The median Tmax values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily. In healthy subjects, a high-fat meal did not affect the drug exposure but reduced the rate of mitapivat absorption, with a 42% reduction in Cmax and a delay in Tmax of 2.3 hours when compared to dosing under fasted conditions. Mitapivat is primary eliminated via hepatic metabolism. After a single oral administration of radiolabeled mitapivat in healthy subjects, the total recovery of administered radioactive dose was 89.2%. About 49.6% of radioactivity was recovered in the urine with 2.6% excreted as unchanged mitapivat. About 39.6% of radioactivity was recovered in the feces with less than 1% being the unchanged drug. The mean volume of distribution at steady state (Vss) was 42.5 L. Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and 14.4 L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively. Metabolism / Metabolites According to _in vitro_ studies, mitapivat is primarily metabolized by CYP3A4. It is also a substrate of CYP1A2, CYP2C8, and CYP2C9. Following a single oral dose administration of 120 mg of radiolabeled mitapivat in healthy subjects, unchanged mitapivat was the major circulating component in plasma. Biological Half-Life In patients with pyruvate kinase deficiency receiving multiple doses of 5 mg mitapivat twice daily to 20 mg twice daily, the mean effective half-life (t1/2) of mitapivat ranged from 3 to 5 hours. |
| Toxicity/Toxicokinetics |
Protein Binding
Mitapivat is 97.7% bound to plasma proteins, with an RBC-to-plasma ratio of 0.37. |
| References |
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| Additional Infomation |
Pharmacodynamics
Mitapivat is a pyruvate kinase activator that works to increase the activity of erythrocyte pyruvate kinase, an enzyme responsible for energy production for and survival of red blood cells. It is effective in upregulating the activity of both wild-type and mutant forms of erythrocyte pyruvate kinase. Interestingly, mitapivat is a mild-to-moderate inhibitor of the aromatase enzyme (CYP19A1), which is an enzyme involved in biosynthesis of estrogens from androgen precursors. Inhibition of aromatase is associated with bone density loss, as estrogen mediates suppressive, antiresorptive effects on osteoclasts and generally favours bone formation over resorption. Thus, low estrogen levels can increase bone turnover and osteoclast activity, resulting in net bone loss and decreased bone quality. Inhibition of aromatase by mitapivat may have some clinical implications, as patients with pyruvate kinase deficiency have considerably high rate of osteopenia and osteoporosis. The long-term effect of mitapivant on bond mineral density requires further investigation. One study suggests that this off-target effect may have negligible clinical effects on adults, but may potentially have some clinical implications in developing children. |
| Molecular Formula |
C24H26N4O3S
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|---|---|
| Molecular Weight |
450.56
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| Exact Mass |
450.173
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| CAS # |
1260075-17-9
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| Related CAS # |
2151847-10-6 (sulfate hydrate);1260075-17-9 (free);2329710-91-8 (sulfate);
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| PubChem CID |
59634741
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| Appearance |
White to off-white solid powder
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| LogP |
4.233
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
32
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| Complexity |
750
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
XAYGBKHKBBXDAK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H26N4O3S/c29-24(28-15-13-27(14-16-28)17-18-6-7-18)20-8-10-21(11-9-20)26-32(30,31)22-5-1-3-19-4-2-12-25-23(19)22/h1-5,8-12,18,26H,6-7,13-17H2
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| Chemical Name |
N-{4-[4-(cyclopropylmethyl)piperazine-1-carbonyl]phenyl}quinoline-8-sulfonamide
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| Synonyms |
PKM2 activator 1020; AG348; PKM2 activator; PKR-IN-1; AG-348; PKR-IN-1; trade name Pyrukynd
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.55 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.55 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2195 mL | 11.0973 mL | 22.1946 mL | |
| 5 mM | 0.4439 mL | 2.2195 mL | 4.4389 mL | |
| 10 mM | 0.2219 mL | 1.1097 mL | 2.2195 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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