| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg | |||
| Other Sizes |
| Targets |
PDE9[1]
The primary target of Irsenontrine is the phosphodiesterase 9 (PDE9) enzyme. It acts as a selective and potent inhibitor, binding to the enzyme's active site to prevent the hydrolysis of cGMP. This specificity for PDE9 over other PDE family members is crucial for its pharmacological profile and its utility as a research tool. |
|---|---|
| ln Vitro |
An oral, specific, and potent inhibitor of phosphodiesterase 9 (PDE 9) is irsenontrine (E2027)[3].
The most detailed in vitro data is available for the more potent R-enantiomer, (R)-Irsenontrine, which has an IC50 of 0.041 microM (41 nM). By extension, Irsenontrine is expected to be a selective PDE9 inhibitor as well, increasing cGMP levels in cells where PDE9 is the dominant phosphodiesterase, such as neurons in certain brain regions. |
| ln Vivo |
In rats given Scopolamine, irsenontrine (0.3, 3.3 mg/kg; po) significantly reduces the proportion of the rats' investigation of the new object[1]. The combined treatment group of memantine hydrochloride (1 mg/kg; po) and irsenontrine (1 mg/kg; po) shows a considerably higher percentage of novel object exploration than memantine hydrochloride (1 mg/kg) alone[1].
The primary rationale for using Irsenontrine is for in vivo research. The compound is described as an "orally active" and "selective" PDE9 inhibitor. While specific data on its efficacy in disease models is not provided in these datasheets, its stated use for "the research of neurological diseases" strongly implies it has been used in vivo to elevate cGMP in the brain and produce positive effects in models of conditions like Alzheimer's disease or schizophrenia. |
| Enzyme Assay |
To demonstrate its mechanism of action, a non-cellular enzyme assay is used. Recombinant human PDE9 is incubated with the compound for 15 minutes at room temperature. Then, 3H-cGMP is added as a substrate, and the mixture is incubated for 20 minutes. The reaction is terminated, and the amount of 3H-5'-GMP product is measured using a scintillation proximity assay (SPA) to calculate the inhibition (IC50).
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| Cell Assay |
To confirm target engagement in a cellular context, a primary neuronal culture or a cell line known to express high levels of PDE9 can be used. The cells are treated with Irsenontrine for a defined period. After treatment, the cells are lysed, and the levels of cGMP are measured using a competitive ELISA kit. An increase in the intracellular cGMP concentration relative to the vehicle control indicates PDE9 inhibition.
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| Animal Protocol |
An in vivo protocol for assessing the activity of a PDE9 inhibitor typically involves oral gavage administration to rodents. For example, mice or rats are fasted overnight, then given a single dose of Irsenontrine suspended in a vehicle like 0.5% methylcellulose. At various time points (e.g., 1, 3, 6, and 24 hours) post-dosing, animals are euthanized. Brain tissue (e.g., cortex or hippocampus) and cerebrospinal fluid are collected and analyzed for cGMP levels by LC-MS/MS or ELISA.
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| ADME/Pharmacokinetics |
Irsenontrine is described as "orally active," which is the key pharmacokinetic property highlighted. This means that when administered orally, it is absorbed from the gastrointestinal tract, enters the bloodstream, and is distributed to its site of action, such as the central nervous system. No other PK parameters, such as half-life or bioavailability, are detailed in these sources.
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| Toxicity/Toxicokinetics |
Toxicological data for Irsenontrine is not provided in these references. As a research compound, a standard safety assessment would include in vitro toxicity screening in a panel of human cell lines and an in vivo tolerability study in rodents, where general health and behavior are monitored for a period after single and repeat doses.
|
| References | |
| Additional Infomation |
Irsenontrine is being studied in the clinical trial NCT03467152 (a study evaluating the efficacy, safety and tolerability of E2027 (hereinafter referred to as Irsenontrine) in patients with Lewy body dementia).
Irsenontrine (E2027) was in clinical development for the treatment of Alzheimer's disease. The therapeutic hypothesis was that increasing cGMP levels in the brain would enhance synaptic plasticity and cognitive function, potentially slowing the progression of the disease. This illustrates how a PDE9 inhibitor can be applied to a major neurodegenerative disorder. |
| Molecular Formula |
C22H22N4O3
|
|---|---|
| Molecular Weight |
390.435084819794
|
| Exact Mass |
390.169
|
| CAS # |
1429509-82-9
|
| Related CAS # |
(R)-Irsenontrine;1429509-81-8;Irsenontrine maleate;1630083-70-3
|
| PubChem CID |
136253996
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| Appearance |
White to off-white solid powder
|
| LogP |
2.4
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
29
|
| Complexity |
619
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
O1CC[C@@H](C1)N1C2=C(C(NC3C=C(C4C(C)=CN=C(C=4C)OC)C=CC2=3)=O)C=N1
|
| InChi Key |
CKJDCNZBABIEBZ-HNNXBMFYSA-N
|
| InChi Code |
InChI=1S/C22H22N4O3/c1-12-9-23-22(28-3)13(2)19(12)14-4-5-16-18(8-14)25-21(27)17-10-24-26(20(16)17)15-6-7-29-11-15/h4-5,8-10,15H,6-7,11H2,1-3H3,(H,25,27)/t15-/m0/s1
|
| Chemical Name |
7-(2-methoxy-3,5-dimethylpyridin-4-yl)-1-[(3S)-oxolan-3-yl]-5H-pyrazolo[4,3-c]quinolin-4-one
|
| 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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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: 12.5 mg/mL (32.02 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (3.20 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), suspension solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 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: ≥ 1.25 mg/mL (3.20 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 12.5 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: ≥ 1.25 mg/mL (3.20 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 | 2.5612 mL | 12.8061 mL | 25.6121 mL | |
| 5 mM | 0.5122 mL | 2.5612 mL | 5.1224 mL | |
| 10 mM | 0.2561 mL | 1.2806 mL | 2.5612 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/NCT04764669
Conditions:Lewy Body Disease|Parkinson DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT03467152
Conditions:Dementia With Lewy BodiesLink: https://clinicaltrials.gov/ct2/show/NCT04023877
Conditions:Dementias With Lewy Bodies
Title:A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E2027 in Healthy Subjects
Status:Completed
updateDate:2018-09-07
Ctid:NCT02873156
Link: https://clinicaltrials.gov/ct2/show/NCT02873156
Conditions:Healthy SubjectsLink: https://clinicaltrials.gov/ct2/show/NCT02415790
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT02947711
Conditions:Healthy SubjectsProducts are for research use only; We do not sell to patients
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