| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| Targets |
The primary target of RIP1 kinase inhibitor 1 is receptor-interacting protein 1 (RIP1) kinase, a key regulator of necroptosis, a form of programmed cell death. RIP1 kinase plays a critical role in the activation of the necroptosis pathway through its interaction with RIP3 and subsequent phosphorylation of MLKL. RIP1 kinase inhibitor 1 binds to RIP1 kinase with high affinity, as indicated by its pKi of 9.04. By inhibiting RIP1 kinase activity, the compound blocks necroptotic cell death and MLKL phosphorylation. RIP1 is also involved in inflammatory signaling, making it a target of interest for neurodegenerative and inflammatory diseases.
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| ln Vitro |
Human colorectal adenocarcinoma HT-29 cells (necroptosis, IC50=2 nM; pMLKL, IC50=1.3 nM) and mouse L cells and MLKL (pMLKL) phosphorylate NCTC 929 (necroptosis, IC50=15 nM; pMLKL, IC50=2.7 nM) are both significantly inhibited by RIP1 kinase inhibitor 1 (compound 22).
In vitro studies demonstrate that RIP1 kinase inhibitor 1 is a highly potent inhibitor of RIP1 kinase with a pKi of 9.04. It strongly suppresses necroptotic cell death and MLKL phosphorylation with an IC₅0 of 2 nM for necroptosis and 1.3 nM for pMLKL in human cells. In mouse L-cells (NCTC 929), it shows IC₅0 values of 15 nM for necroptosis and 2.7 nM for pMLKL. These potent inhibitory effects make RIP1 kinase inhibitor 1 a valuable tool for studying RIP1 biology and its role in necroptosis, inflammation, and neurodegenerative diseases. |
| ln Vivo |
In vivo studies of RIP1 kinase inhibitor 1 are focused on evaluating its efficacy in animal models of diseases where RIP1 kinase plays a role, such as neurodegenerative diseases, inflammatory conditions, and ischemic injury. The compound is orally available and brain-penetrating, making it suitable for studying central nervous system disorders. Its excellent PK profiles support its use in in vivo studies. RIP1 kinase inhibitor 1 may be used to validate RIP1 as a therapeutic target in various disease models. Further in vivo studies are needed to fully characterize its efficacy, safety, and pharmacokinetic profile.
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| Enzyme Assay |
For in vitro enzyme/receptor binding assays, RIP1 kinase inhibitor 1 is evaluated using kinase activity assays that measure RIP1-mediated phosphorylation. The compound is incubated with recombinant RIP1 kinase and ATP at various concentrations. RIP1 kinase activity is quantified by measuring phosphorylation of peptide substrates using radiometric, fluorescence-based, or ELISA methods. Binding affinity (pKi) is determined using competitive binding assays. IC₅0 values for inhibition of necroptosis and MLKL phosphorylation are determined in cell-based assays. Selectivity profiling against other kinases may be performed to confirm specificity.
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| Cell Assay |
For in vitro cellular experiments, RIP1 kinase inhibitor 1 is tested in cell lines that undergo necroptosis upon stimulation, such as L929 or U937 cells. Cells are cultured in appropriate media and treated with various concentrations of the compound (typically ranging from picomolar to micromolar) in the presence of necroptosis inducers (such as TNF-alpha, SMAC mimetic, and z-VAD-fmk). Cell death is assessed using viability assays such as MTT or PI staining. MLKL phosphorylation is measured by Western blotting. The compound's effects on RIP1-dependent signaling pathways are further investigated.
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| Animal Protocol |
For in vivo animal experiments, RIP1 kinase inhibitor 1 can be administered to rodents via oral gavage, taking advantage of its oral bioavailability. The compound's brain-penetrating properties support its use in models of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, or traumatic brain injury. Typical dosing regimens may range from 1 to 50 mg/kg administered daily or intermittently. Disease progression, behavioral outcomes, and inflammatory markers are assessed. Pharmacodynamic markers such as MLKL phosphorylation are measured in tissues.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of RIP1 kinase inhibitor 1 include oral availability and excellent PK profiles, supporting its use in oral administration studies. The compound is brain-penetrating, making it suitable for studying central nervous system disorders. As a small molecule with a molecular weight of 461.90 g/mol, it is likely to have reasonable absorption and distribution characteristics. Detailed parameters such as Cₘₐₓ, Tₘₐₓ, AUC, half-life, and clearance would need to be determined through comprehensive PK studies. The compound's metabolism and excretion pathways remain to be fully characterized.
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| Toxicity/Toxicokinetics |
Toxicological data for RIP1 kinase inhibitor 1 are limited, as it is primarily a research tool. As a RIP1 kinase inhibitor, its toxicity would depend on the importance of RIP1 for normal cellular function. RIP1 is involved in cell death and inflammatory signaling, and its inhibition could have effects on immune function and tissue homeostasis. Comprehensive toxicology studies including acute and repeated-dose toxicity, genotoxicity, and cardiotoxicity assessments would be needed for further development. Appropriate safety precautions should be taken when handling this compound, including the use of personal protective equipment and adherence to institutional safety guidelines.
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| References | |
| Additional Infomation |
RIP1 kinase inhibitor 1 is a research compound used to study RIP1 biology and develop therapies for neurodegenerative, inflammatory, and ischemic diseases. No clinical trials or regulatory approvals have been reported for this compound as a therapeutic agent. It is available from various chemical suppliers for research purposes only. The compound is a highly potent, orally available, and brain-penetrating RIP1 kinase inhibitor with a pKi of 9.04. It strongly suppresses necroptotic cell death and MLKL phosphorylation with IC₅0 values of 2 nM and 1.3 nM in human cells.
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| Molecular Formula |
C24H20CLN5O3
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|---|---|
| Molecular Weight |
461.9003
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| Exact Mass |
461.125
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| CAS # |
2095515-38-9
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| Related CAS # |
2095515-38-9;
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| PubChem CID |
132471860
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| Appearance |
White to yellow solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
33
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| Complexity |
811
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1=C2C(C(N(C([H])([H])C2([H])[H])[C@]2([H])C(N(C([H])([H])[H])C3C([H])=C([H])C(C#N)=C([H])C=3OC2([H])[H])=O)=O)=NN1C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H]
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| InChi Key |
JWKONLKXWPCOJF-IBGZPJMESA-N
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| InChi Code |
InChI=1S/C24H20ClN5O3/c1-28-18-8-7-16(12-26)11-20(18)33-14-19(23(28)31)29-10-9-17-21(24(29)32)27-30(22(17)25)13-15-5-3-2-4-6-15/h2-8,11,19H,9-10,13-14H2,1H3/t19-/m0/s1
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| Chemical Name |
(3S)-3-(2-benzyl-3-chloro-7-oxo-4,5-dihydropyrazolo[3,4-c]pyridin-6-yl)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepine-8-carbonitrile
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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 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 : ~200 mg/mL (~432.99 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 5 mg/mL (10.82 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 50.0 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: ≥ 5 mg/mL (10.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1650 mL | 10.8249 mL | 21.6497 mL | |
| 5 mM | 0.4330 mL | 2.1650 mL | 4.3299 mL | |
| 10 mM | 0.2165 mL | 1.0825 mL | 2.1650 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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