| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
MPO[1]
Myeloperoxidase (MPO) (IC50: 1.5 nM), Thyroid peroxidase (TPO) (IC50: 0.69 uM) |
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| ln Vitro |
In vitro biochemical assays demonstrate that Mitiperstat potently inhibits human myeloperoxidase (MPO) with an IC50 of 1.5 nM. The compound exhibits selectivity for MPO over thyroid peroxidase (TPO) by >450-fold (IC50 = 0.69 uM). It also shows a weak inhibitory activity against CYP3A4 with an IC50 of 6 uM, suggesting a low risk of clinically significant drug-drug interactions via this pathway. Mitiperstat is an irreversible inhibitor, covalently modifying the active site heme moiety or essential cysteine residues.
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| ln Vivo |
In preclinical disease models, Mitiperstat inhibits extracellular myeloperoxidase activity, decreases inflammation, and improves microvascular function. The compound has been investigated in Phase 2 clinical trials for heart failure with preserved or mildly reduced ejection fraction and for non-alcoholic fatty liver disease (NAFLD). In animal models, dose-dependent inhibition of MPO activity has been demonstrated (e.g., in zymosan-induced neutrophilic peritonitis in BALB/c mice). It has shown potential in reducing oxidative stress and preserving cardiac function.
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| Enzyme Assay |
Recombinant human myeloperoxidase (MPO) or MPO isolated from human neutrophils is used. The enzyme activity assay measures the peroxidase activity of MPO using a chromogenic or fluorogenic substrate. A typical assay uses Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine) as substrate in the presence of hydrogen peroxide (H2O2). The reaction is incubated at room temperature or 37degC for 10-30 minutes in phosphate-buffered saline (PBS, pH 7.4). The product (resorufin) is measured by fluorescence (excitation 530-560 nm, emission 585-590 nm) or absorbance (570 nm). Alternatively, a TMB (tetramethylbenzidine) or ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) assay can be used. Mitiperstat is pre-incubated with the enzyme for 5-10 minutes before substrate addition to allow for irreversible binding. IC50 values are calculated from dose-response curves (1.5 nM). Selectivity against thyroid peroxidase (TPO) and other peroxidases is assessed similarly. For CYP3A4 inhibition, a standard CYP inhibition assay using a fluorogenic substrate (e.g., dibenzylfluorescein) or LC-MS/MS probe substrate (midazolam) is performed.
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| Cell Assay |
For cellular MPO inhibition studies, human neutrophils or HL-60 cells differentiated into neutrophil-like cells are used. Cells are cultured in RPMI-1640 with 10% FBS and differentiated with DMSO (1.25%) for 5-7 days. Cells are treated with Mitiperstat (0.1-1000 nM) for 1-4 hours, then stimulated with phorbol 12-myristate 13-acetate (PMA, 100 nM) or opsonized zymosan to activate MPO release and activity. MPO activity in the supernatant is measured using the Amplex Red/H2O2 assay as described above. Cell viability is assessed by trypan blue exclusion or MTT assay. Myeloperoxidase protein levels can be quantified by ELISA. Intracellular reactive oxygen species (ROS) production can be measured using DCFH-DA fluorescent probe. The effect of MPO inhibition on neutrophil extracellular trap (NET) formation can also be assessed by fluorescence microscopy.
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| Animal Protocol |
In vivo efficacy studies are typically conducted in BALB/c mice or other rodent models. For the neutrophilic peritonitis model: mice are administered Mitiperstat (0.1-10 mg/kg) orally or intraperitoneally. After 1-2 hours, zymosan (0.5-1 mg) or thioglycollate (2-4%) is injected intraperitoneally to induce neutrophil recruitment. After 4-6 hours, peritoneal lavage fluid is collected. MPO activity in the lavage fluid is measured using the Amplex Red assay. In cardiovascular models: mice or rats are administered Mitiperstat (1-10 mg/kg/day orally) for 2-8 weeks. Endpoints include echocardiographic assessment of cardiac function (ejection fraction, fractional shortening), plasma biomarkers (NT-proBNP, troponin), inflammatory markers (IL-6, TNF-alpha, MPO), and oxidative stress markers (8-isoprostane, protein carbonylation). Histological analysis of heart tissue (H&E, Masson's trichrome for fibrosis) is performed. In NAFLD models: high-fat diet-fed mice are treated with Mitiperstat (1-10 mg/kg/day orally) for 8-12 weeks; endpoints include liver histology (steatosis, inflammation, fibrosis), plasma ALT/AST, and hepatic triglyceride content.
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| ADME/Pharmacokinetics |
Mitiperstat displays moderate clearance and high oral bioavailability in rats, as reported in the literature. Detailed pharmacokinetic parameters in humans have been studied in Phase 1 clinical trials: following oral administration, Mitiperstat is absorbed with a Tmax of approximately 1-2 hours. The terminal half-life is suitable for once-daily dosing. AUC and Cmax are dose-proportional over the therapeutic dose range. Plasma protein binding is moderate to high. Metabolism is primarily via CYP3A4-mediated oxidation, and Mitiperstat shows weak CYP3A4 inhibition (IC50 6 uM), suggesting a low risk of drug-drug interactions. The compound is eliminated primarily in feces and urine as metabolites. Full PK data are available in clinical trial reports and regulatory documents.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies in multiple species (rat, dog) have established an acceptable safety margin for Mitiperstat. In clinical trials, Mitiperstat has been generally well tolerated. Common adverse events reported include mild gastrointestinal disturbances (nausea, diarrhea). No significant drug-induced liver injury (DILI), cardiotoxicity (QT prolongation), or genotoxicity has been observed at therapeutic doses. The no-observed-adverse-effect level (NOAEL) has been determined in 28-day and 90-day toxicology studies. As an MPO inhibitor, the primary expected on-target effect is modulation of oxidative stress and inflammation, which is the intended therapeutic mechanism. Long-term safety data from ongoing clinical trials will further characterize the risk-benefit profile.
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| References | |
| Additional Infomation |
Mitiperstat is being investigated in the clinical trial NCT05492877 (Efficacy and safety study of Mitiperstat (AZD4831) (myeloperoxidase inhibitor) versus placebo in the treatment of moderate to severe COPD). Mitiperstat is a myeloperoxidase inhibitor; its structure is shown in reference 23.
Mitiperstat (AZD4831) is an orally bioavailable, irreversible myeloperoxidase (MPO) inhibitor developed by AstraZeneca. MPO is a key enzyme in the innate immune system that produces hypochlorous acid and other reactive oxidants; its overactivity is implicated in cardiovascular diseases, including heart failure with preserved ejection fraction (HFpEF), coronary artery disease, and atherosclerosis, as well as inflammatory conditions such as NAFLD and COPD. Mitiperstat has completed Phase 1 clinical trials and has advanced into Phase 2 studies for heart failure and NAFLD. As of current information, it is not yet approved for clinical use; development status may have changed. Molecular formula: C15H15ClN4OS, molecular weight: 334.82. The compound is (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one. References: Tord Inghardt, et al. J Med Chem. 2022; US Patent 20160152623A1. For research use only. |
| Molecular Formula |
C15H15CLN4OS
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|---|---|
| Molecular Weight |
334.82
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| Exact Mass |
334.065
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| CAS # |
1933460-19-5
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| PubChem CID |
121362450
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| Appearance |
Off-white to pink solid powder
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
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| Complexity |
463
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1(=S)NC(=O)C2NC=CC=2N1CC1=CC=C(Cl)C=C1[C@H](N)C
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| InChi Key |
BHKKSKOHRFHHIN-MRVPVSSYSA-N
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| InChi Code |
InChI=1S/C15H15ClN4OS/c1-8(17)11-6-10(16)3-2-9(11)7-20-12-4-5-18-13(12)14(21)19-15(20)22/h2-6,8,18H,7,17H2,1H3,(H,19,21,22)/t8-/m1/s1
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| Chemical Name |
1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one
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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: 125 mg/mL (373.33 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9867 mL | 14.9334 mL | 29.8668 mL | |
| 5 mM | 0.5973 mL | 2.9867 mL | 5.9734 mL | |
| 10 mM | 0.2987 mL | 1.4933 mL | 2.9867 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.
Link: https://clinicaltrials.gov/ct2/show/NCT05492877
Conditions:Chronic Obstructive Pulmonary Disease (COPD)Link: https://clinicaltrials.gov/ct2/show/NCT04986202
Conditions:Heart Failure With Preserved Ejection FractionLink: https://clinicaltrials.gov/ct2/show/NCT05638737
Conditions:Non-Cirrhotic Non-alcoholic Steatohepatitis With Fibrosis
Title:Myeloperoxidase (MPO) Inhibitor A_Zeneca for Heart Failure With Preserved Ejection Fraction (HFpEF)
Status:Completed
updateDate:2025-01-08
Ctid:NCT03611153
Link: https://clinicaltrials.gov/ct2/show/NCT03611153
Conditions:Heart FailureLink: https://clinicaltrials.gov/ct2/show/NCT05751759
Conditions:Hepatic ImpairmentLink: https://clinicaltrials.gov/ct2/show/NCT05457270
Conditions:Healthy VolunteersLink: https://clinicaltrials.gov/ct2/show/NCT05236543
Conditions:Healthy VolunteersLink: https://clinicaltrials.gov/ct2/show/NCT04949438
Conditions:Renal ImpairmentLink: https://clinicaltrials.gov/ct2/show/NCT05052710
Conditions:Healthy VolunteersLink: https://clinicaltrials.gov/ct2/show/NCT03756285
Conditions:Heart FailureLink: https://clinicaltrials.gov/ct2/show/NCT04232345
Conditions:Heart Failure With Preserved Ejection Fraction (HFpEF)Link: https://clinicaltrials.gov/ct2/show/NCT03136991
Conditions:Cardiovascular DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT02712372
Conditions:Cardiovascular DiseaseProducts are for research use only; We do not sell to patients
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