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| Targets |
Inflachromene targets HMGB1 and HMGB2, two high mobility group proteins that act as pro-inflammatory mediators when released from cells. It directly binds to these proteins and reduces their cytoplasmic accumulation in microglial cells. Inflachromene also targets and inhibits the TRPV4 ion channel. By inhibiting these targets, it exerts its anti-inflammatory and neuroprotective effects.
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| ln Vitro |
Without causing harm to BV-2 microglia, inflachromene (0.01-100 μM) efficiently inhibits LPS-induced nitrite emission in a dose-dependent manner over a 24-hour period [2]. After LPS stimulation, inflamachromene (1–10 μM) can prevent the upregulation of genes linked to inflammation (including Il6, Il1b, Nos2, and Tnf) [2]. LPS-induced production of the pro-inflammatory cytokine TNF-α is inhibited by inflachromene (5 μM) [2]. Inflachromene (5 μM; 30 minutes) strongly prevents NF-κB from moving to the nucleus and IκB from degrading [2]. In microglia, LPS-induced activation of ERK, JNK, and p38 MAPK is inhibited by inflachromene (1–10 μM; 30 minutes) [2]. By blocking microglia-mediated neurotoxicity, inflachromene (10 μM; 30 min) totally prevents co-cultured neuroblastoma and primary neuronal cells from dying [2]. Neuronal viability is not significantly affected by inflachromene (1–10 μM; 24 hours) [2].
Inflachromene efficiently blocks LPS-induced inflammation in vitro. It binds to HMGB1 and HMGB2 and reduces their cytoplasmic accumulation in microglial cells. It effectively downregulates the pro-inflammatory function of HMGB and reduces neuronal damage. Its anti-inflammatory activity has been confirmed in various in vitro models. |
| ln Vivo |
Inflachromene (2-10 mg/kg; intraperitoneally injected once day for 4 days) can effectively prevent LPS-mediated microglial activation [2]. Inflachromene (10 mg/kg; intraperitoneally injected once daily for 30 days) significantly delayed illness progression as assessed by EAE clinical scores [2]. Inflachromene (1 mg/kg; iv) has a long half-life (14.1±6.43 h) and moderate Vss (2.02±1.02 L/kg)[1]. Inflachromene (1 mg/kg; po) has high oral bioavailability (94%) and Cmax (0.59±0.16 g/mL) [1].
Inflachromene is functional in vivo, downregulating pro-inflammatory functions of HMGB proteins and reducing neuronal damage. It also ameliorates inflammatory pathogenesis in a mouse model of sepsis. Its ability to inhibit microglial-mediated neuroinflammation makes it a promising candidate for the treatment of neuroinflammatory disorders. |
| Enzyme Assay |
The primary in vitro assays for Inflachromene include binding assays to measure its affinity for HMGB1 and HMGB2. These can be performed using techniques such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). Its anti-inflammatory activity is assessed in cell-based assays by measuring its ability to inhibit LPS-induced inflammation in microglial cells.
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| Cell Assay |
In vitro cellular experiments involve treating microglial cells with Inflachromene and measuring its effects on HMGB1 and HMGB2 accumulation and the production of pro-inflammatory cytokines. The compound's ability to reduce neuronal damage can be assessed in co-culture systems of microglia and neurons. Its effects on TRPV4 activity can be measured using calcium imaging or electrophysiology.
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| Animal Protocol |
Animal/Disease Models: Treatment of male C57BL/6 mice (11 weeks; 25-30 g) with LPS[2]
Doses: 2, 10 mg/kg Route of Administration: intraperitoneal (ip) injection one time/day for 4 days Experimental Results: Blockade LPS-mediated microglial activation even at a dose of 2 mg/kg. Animal/Disease Models: SD (SD (Sprague-Dawley)) rat (7 weeks; 230-250 g) [1] Doses: 1 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: IV and Oral Experimental Results: IV: t1 /2=14.1±6.43 hrs (hrs (hours)); CL=0.14±0.01L/kg/hour; Vss=2.02±1.02L/kg. Po: t1/2=7.96±1.16h; F=94%; Cmax=0.59±0.16g/mL. In vivo animal experiments have been conducted using a mouse model of sepsis, where Inflachromene ameliorated inflammatory pathogenesis. Its effects on neuroinflammation could be evaluated in models of neurodegenerative diseases or epilepsy. These studies would assess its ability to reduce inflammation, neuronal damage, and disease severity. |
| ADME/Pharmacokinetics |
Inflachromene has a molecular weight of 377.39 g/mol and a molecular formula of C21H19N3O4. It is soluble in ethanol (2.5 mg/mL), DMSO (30 mg/mL), and DMF. It is typically stored at -20°C. Its purity is ≥95%.
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| Toxicity/Toxicokinetics |
The toxicological profile of Inflachromene is not extensively detailed in the provided sources. As a research compound, it is not intended for human use. Standard safety precautions should be followed when handling. Its safety would need to be established through preclinical studies if it were to be developed for therapeutic applications.
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| References |
[1]. Lee HH, et, al. A validated UPLC-MS/MS method for pharmacokinetic study of inflachromene, a novel microglia inhibitor. J Pharm Biomed Anal. 2019 Mar 20; 166: 183-188.
[2]. Lee S, et, al. A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. Nat Chem Biol. 2014 Dec; 10(12): 1055-60. |
| Additional Infomation |
Inflachromene (ICM) is a microglial inhibitor that directly binds HMGB1 and HMGB2, reducing their cytoplasmic accumulation and downregulating their pro-inflammatory functions. It is used in the research of neuroinflammatory disorders and epilepsy. Inflachromene also targets the TRPV4 ion channel. It has shown efficacy in a mouse model of sepsis. It is available from various chemical suppliers for research purposes.
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| Molecular Formula |
C21H19N3O4
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| Molecular Weight |
377.4
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| Exact Mass |
377.137
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| CAS # |
908568-01-4
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| PubChem CID |
49857340
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| Appearance |
White to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
532.6±60.0 °C at 760 mmHg
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| Flash Point |
275.9±32.9 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.747
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| LogP |
1.86
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
28
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| Complexity |
714
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1N2CC=C3C(C)(C)OC4C(=CC=C(C=4)O)C3N2C(=O)N1C1C=CC=CC=1
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| InChi Key |
VVOXDJYPDCSQMI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H19N3O4/c1-21(2)16-10-11-22-19(26)23(13-6-4-3-5-7-13)20(27)24(22)18(16)15-9-8-14(25)12-17(15)28-21/h3-10,12,18,25H,11H2,1-2H3
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| Chemical Name |
5-hydroxy-9,9-dimethyl-15-phenyl-8-oxa-13,15,17-triazatetracyclo[8.7.0.02,7.013,17]heptadeca-2(7),3,5,10-tetraene-14,16-dione
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| Synonyms |
ICM; Inflachromene
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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 : ~100 mg/mL (~264.98 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.62 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 (6.62 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 (6.62 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 | 2.6497 mL | 13.2485 mL | 26.4971 mL | |
| 5 mM | 0.5299 mL | 2.6497 mL | 5.2994 mL | |
| 10 mM | 0.2650 mL | 1.3249 mL | 2.6497 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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