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| Targets |
RIPK
The primary target of Necroptosis-IN-1 is RIPK1 (receptor interacting protein kinase 1), a key regulator of the necroptosis signaling pathway. By inhibiting RIPK1, the compound blocks the formation of the necrosome complex and prevents the execution of necroptosis. The compound is an analog of Necrostatin-1, a well-characterized RIPK1 inhibitor. It does not significantly affect apoptosis or other cell death pathways. |
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| ln Vitro |
Necrotic cell death is prevalent in many different pathological disease states and in traumatic injury. Necroptosis is a form of necrosis that stems from specific signaling pathways, with the key regulator being receptor interacting protein 1 (RIP1), a serine/threonine kinase. Specific inhibitors of RIP1, termed necrostatins, are potent inhibitors of necroptosis. Necrostatins are structurally distinct from one another yet still possess the ability to inhibit RIP1 kinase activity. To further understand the differences in the binding of the various necrostatins to RIP1 and to develop a robust high-throughput screening (HTS) assay, which can be used to identify new classes of RIP1 inhibitors, we synthesized fluorescein derivatives of Necrostatin-1 (Nec-1) and Nec-3. These compounds were used to establish a fluorescence polarization (FP) assay to directly measure the binding of necrostatins to RIP1 kinase. The fluorescein-labeled compounds are well suited for HTS because the assays have a dimethyl sulfoxide (DMSO) tolerance up to 5% and Z' scores of 0.62 (fluorescein-Nec-1) and 0.57 (fluorescein-Nec-3). In addition, results obtained from the FP assays and ligand docking studies provide insights into the putative binding sites of Nec-1, Nec-3, and Nec-4.[1]
In vitro, Necroptosis-IN-1 demonstrates potent inhibition of necroptosis. As a RIPK inhibitor, it blocks the necroptosis signaling pathway and prevents cell death in response to necroptotic stimuli. The compound is an analog of Necrostatin-1 and shows similar or improved activity in cellular models. The exact IC₅₀ values for RIPK1 inhibition and necroptosis inhibition are not provided in the available literature. |
| ln Vivo |
In vivo activity of Necroptosis-IN-1 has not been extensively characterized. As a necroptosis inhibitor, it has potential for studying the role of necroptosis in various disease models, including inflammatory diseases and neurodegenerative disorders. However, detailed in vivo efficacy and pharmacokinetic data are limited in the available literature. The compound's activity as a RIPK inhibitor suggests it may have in vivo activity.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for Necroptosis-IN-1 typically involve RIPK1 kinase activity studies. The enzyme is incubated with varying concentrations of Necroptosis-IN-1 (0.01-100 µM) in appropriate buffer. Kinase activity is measured using radioactive or fluorescent substrates, and the IC₅₀ value is calculated from the dose-response curve. The compound demonstrates concentration-dependent inhibition of RIPK1 activity.
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| Cell Assay |
In vitro cellular assays for Necroptosis-IN-1 involve testing its effects on necroptosis in cell models. Cells (e.g., HT-29, L929) are treated with necroptotic stimuli (TNF-α + zVAD + SM-164 or similar) in the presence of varying concentrations of Necroptosis-IN-1 (0.01-100 µM). Cell death is measured by LDH release, propidium iodide staining, or MTT assays after 24-48 hours. The compound demonstrates concentration-dependent inhibition of necroptosis.
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| Animal Protocol |
In vivo animal studies for Necroptosis-IN-1 are limited, as the compound is primarily used in research to study necroptosis. For efficacy testing, animal models of inflammatory diseases or ischemia-reperfusion injury could be used. Animals would be treated with Necroptosis-IN-1 via oral or intraperitoneal administration at various doses. However, detailed in vivo protocols are not well established in the available literature.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of Necroptosis-IN-1 include a molecular weight of 263.68 and a molecular formula of C₁₂H₁₀ClN₃O₂. The compound is intended for research use only and has not been approved for clinical use. Detailed pharmacokinetic parameters such as half-life, oral bioavailability, and tissue distribution are not well characterized in the available literature.
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| Toxicity/Toxicokinetics |
The toxicity profile of Necroptosis-IN-1 has not been extensively characterized. As a research compound, standard toxicity studies would include assessment of acute oral toxicity, repeated-dose toxicity, and genotoxicity in animal models. The compound is intended for research use only and is not approved for clinical use. Further toxicological studies would be needed to fully establish its safety profile for therapeutic applications.
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| References | |
| Additional Infomation |
Necroptosis-IN-1 (CAS 1391980-92-9) has a molecular formula of C₁₂H₁₀ClN₃O₂ and a molecular weight of 263.68. It is an analog of Necrostatin-1 and a potent necroptosis inhibitor that targets RIPK1. The compound blocks the necroptosis signaling pathway and prevents programmed necrosis. It is intended for research use only and is not approved for clinical use. The compound is used to study necroptosis and its role in various diseases.
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| Molecular Formula |
C12H10CLN3O2
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| Molecular Weight |
263.679701328278
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| Exact Mass |
263.046
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| CAS # |
1391980-92-9
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| PubChem CID |
78003872
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| Appearance |
White to light yellow 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 |
2
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
18
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| Complexity |
376
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC=CC2=C1NC=C2CC1C(NC(N1)=O)=O
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| InChi Key |
HAPHEBPGIQHYHN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H10ClN3O2/c13-8-3-1-2-7-6(5-14-10(7)8)4-9-11(17)16-12(18)15-9/h1-3,5,9,14H,4H2,(H2,15,16,17,18)
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| Chemical Name |
5-[(7-chloro-1H-indol-3-yl)methyl]imidazolidine-2,4-dione
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| Synonyms |
Necroptosis-IN-1; 1391980-92-9; 5-((7-chloro-1H-indol-3-yl)methyl)imidazolidine-2,4-dione; 5-[(7-chloro-1H-indol-3-yl)methyl]imidazolidine-2,4-dione; 2,4-Imidazolidinedione, 5-[(7-chloro-1H-indol-3-yl)methyl]-; SCHEMBL15045785;
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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 : 100 mg/mL (379.25 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (7.89 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 20.8 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: ≥ 2.08 mg/mL (7.89 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 20.8 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: ≥ 2.08 mg/mL (7.89 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 | 3.7925 mL | 18.9624 mL | 37.9248 mL | |
| 5 mM | 0.7585 mL | 3.7925 mL | 7.5850 mL | |
| 10 mM | 0.3792 mL | 1.8962 mL | 3.7925 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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