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Purity: ≥98%
Verdiperstat (also known as AZD3241) is a novel, potent, selective, irreversible and orally bioactive myeloperoxidase/MPO inhibitor (IC50 = 630 nM) with the potential to be used in the treatment of neurodegenerative brain disorders. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson's disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of (11)C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson's Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of (11)C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of (11)C-PBR28 binding to translocator protein in the brain of patients with Parkinson's disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders.
| Targets |
Myeloperoxidase (MPO) inhibitor verdiperstat (AZD3241), with an IC50 of 630 nM, is employed in the investigation of neurodegenerative brain illnesses [1]. Myeloperoxidase is specifically and irreversibly inhibited by verdiperstat (AZD3241), which may also play a role in lowering oxidative stress and consequently chronic neuroinflammation [2].
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| ln Vitro |
Myeloperoxidase (MPO) inhibitor verdiperstat (AZD3241), with an IC50 of 630 nM, is employed in the investigation of neurodegenerative brain illnesses [1]. Myeloperoxidase is specifically and irreversibly inhibited by verdiperstat (AZD3241), which may also play a role in lowering oxidative stress and consequently chronic neuroinflammation [2].
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| ln Vivo |
Following intravenous administration of a microdose of carbon-11 labeled Verdiperstat ([11C]AZD3241) in cynomolgus monkeys, there was a rapid presence of radioactivity in the brain. The distribution to the brain was fast, with a maximum concentration (Cmax) corresponding to 1.9% to 2.6% of the injected radioactivity observed within 1.5 minutes post-injection. The radioactivity was homogeneously distributed throughout the brain, followed by a rapid washout. This study confirmed adequate brain exposure of Verdiperstat (AZD3241) in non-human primates. [1]
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| Enzyme Assay |
The IC50 value for Verdiperstat (AZD3241) inhibiting human myeloperoxidase (MPO) was determined to be 630 nmol/L. The assay was based on the physiological enzymatic activity of MPO. [1]
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| Animal Protocol |
A PET microdosing study was performed in three cynomolgus monkeys (1 female, 2 males) to assess the brain exposure of Verdiperstat (AZD3241). Carbon-11 labeled [11C]AZD3241 was synthesized via a multi-step radiochemical procedure. The formulated product for injection was prepared by dissolving the purified [11C]AZD3241 in phosphate-buffered saline (PBS) containing a small volume of ethanol, followed by sterile filtration. Animals were anesthetized and their heads immobilized. A single intravenous bolus injection of [11C]AZD3241 (injected radioactivity: 160 ± 1 MBq, mean ± SD) was administered over 5 seconds via a sural vein, simultaneously with the start of PET data acquisition. Brain radioactivity was measured continuously for 125 minutes using a high-resolution research tomography (HRRT) PET system. No carrier (unlabeled) drug was co-administered; this was a tracer microdose study. [1]
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| ADME/Pharmacokinetics |
In cynomolgus monkeys, the compound rapidly entered the brain after a single intravenous injection of a microdose of [11C]AZD3241. The time to reach maximum concentration in the brain (Tmax) was 1.2 to 1.5 minutes. The maximum concentration in the brain (Cmax) was 1.86% to 2.58% (%ID) of the injected dose. The distribution in the brain was uniform, and the radioactive material was rapidly cleared from the brain. Specific pharmacokinetic parameters such as half-life, clearance, volume of distribution, oral bioavailability, metabolism, and excretion were not reported in this microdose PET study. [1]
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| Toxicity/Toxicokinetics |
In a PET microdose study of cynomolgus monkeys, only a tracer (microdose) of [11C]AZD3241 was administered, and no administration-related adverse reactions were observed. No significant changes were observed in physiological parameters (ECG, heart rate, blood pressure, respiratory rate, oxygen saturation) and blood parameters monitored during the experiment. However, no toxicity data such as LD50, organ toxicity, or protein binding were provided. [1]
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| References |
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| Additional Infomation |
Verdiperstat is currently in clinical trials for basic science and therapeutic research in multiple system atrophy (MSA).
Drug Indications Treatment of Amyotrophic Lateral Sclerosis Treatment of Multiple System Atrophy Verdiperstat (AZD3241) is a pyrrolo[3,2-d]pyrimidin-4-one derivative developed as a potent and selective myeloperoxidase (MPO) inhibitor. It has been selected as a candidate drug to slow the progression of neurodegenerative brain diseases. This study developed a rapid four-step carbon-11 radiolabeling method for labeling AZD3241 to enable PET microdose delivery. Successful synthesis and subsequent PET studies in monkeys demonstrated that AZD3241 rapidly crosses the intact blood-brain barrier and distributes uniformly within the brain. This confirms sufficient exposure of the drug in the brain to support its translation into a Phase IIa clinical trial for patients. The uniform distribution and rapid clearance of the drug in normal monkey brains suggest that nonspecific binding of the drug is lower in regions with low MPO expression. [1] |
| Molecular Formula |
C11H15N3O2S
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|---|---|
| Molecular Weight |
253.320700883865
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| Exact Mass |
253.088
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| CAS # |
890655-80-8
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| PubChem CID |
11528958
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| Appearance |
White to light brown solid powder
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| LogP |
1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
17
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| Complexity |
322
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1N([H])C2C(N([H])C(=S)N(CCOC(C)C)C=2C=1)=O
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| InChi Key |
FVJCUZCRPIMVLB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H15N3O2S/c1-7(2)16-6-5-14-8-3-4-12-9(8)10(15)13-11(14)17/h3-4,7,12H,5-6H2,1-2H3,(H,13,15,17)
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| Chemical Name |
1-[2-(propan-2-yloxy)ethyl]-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
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| Synonyms |
AZD3241; AZD 3241; AZD-3241
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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 (~493.45 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 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 (9.87 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 (9.87 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 | 3.9476 mL | 19.7379 mL | 39.4758 mL | |
| 5 mM | 0.7895 mL | 3.9476 mL | 7.8952 mL | |
| 10 mM | 0.3948 mL | 1.9738 mL | 3.9476 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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