E6446 |
| Catalog No.GC33900 |
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1219925-73-1
Sample solution is provided at 25 µL, 10mM.
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E6446 is a potent and orally acitve TLR7 and TLR9 antagonist, used in the research of deleterious inflammatory responses.
E6446 is a potent and orally acitve TLR7 and TLR9 inhibitor. E6446 potently suppresses DNA stimulation of HEK:TLR9 cells, with an IC50 value of 10 nM, but is significantly less effective at suppressing LPS endotoxin stimulation of HEK:TLR4 cells or R848 stimulation of HEK:TLR7 cells. E6446 potently inhibits IL-6 production induced by CpG2216 but is ineffective against induction by the TLR3 ligand poly inosine-cytosine. The ability of E6446 to inhibit TLR7 is ligand dependent, E6446 is a potent inhibitor of IL-6 induction by RNA but a relatively poor inhibitor of IL-6 induction by the small molecule imidazoquinoline ligand R-848. E6446 suppress TLR9-DNA interaction in vitro, with an IC50 in the 1 to 10 µM range[1]. E6446 (0.01-0.03 μM) specifically inhibits TLR9 activation with CpG ODN 2006, and blocks TLR7/8 activated by the imidazoquinoline compound R848 at 2-8 μM. E6446 reduces 50% of TLR4 activation at 30 μM, and shows IC50s of 0.01 μM and 0.23 μM in HEK-TLR9 cells stimulated with oligo 2006 and in human PBMCs stimulated with oligo 2216, respectively[2].
E6446 (20 mg/kg, p.o.) almost cmlpletely inhibits CpG1668-induced IL-6 production, and dose-dependently suppresses the development of ANA (anti-nuclear antibodies) in mice at 20 and 60 mg/kg[1]. E6446 (20, 60 mg/kg, p.o.) dose-dependently inhibits TLR9 signaling in mice. E6446 (60, 120 mg/kg, p.o.) prevents hyperresponsiveness of TLRs and LPS-induced septic shock in rodent malaria, diminishes TLR responsiveness during acute malaria, suppresses activation of both TLR7 and TLR9[2].
[1]. Lamphier M, et al. Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol. 2014 Mar;85(3):429-40. [2]. Franklin BS, et al. Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3689-94.
Cell experiment: | E6446 is assayed for the suppression of BALB/c mouse spleen interleukin-6 (IL-6) production in response to stimulation by oligonucleotide CpG1668. E6446 is added to dissociated splenocytes (5 × 105 per well in complete RPMI/10% fetal bovine serum in a 96-well plate) before addition of TLR agonists. Cells are stimulated for 72 hours, and supernatants are removed for ELISA analysis of IL-6. Mouse bone marrow-derived dendritic cells (BMDCs) are generated by culturing BALB/c marrow cells in RPMI containing 100 ng/mL Flt3 ligand for 7 days. Cells (1 × 105) in 50 μL are assayed for IL-6 production after overnight or 24-hour stimulation with various TLR ligands. For studies using human peripheral blood mononuclear cells, Ficoll-separated mononuclear cells are isolated from healthy volunteer donors, washed, and plated with stimulatory oligonucleotide CpG2216 in complete RPMI for 72 hours. Interferon in supernatant is quantified by ELISA[1]. |
Animal experiment: | Mice[1]MRL/lpr mice are dosed orally five times a week with 20 or 60 mg/kg E6446 or 60 mg/kg hydroxychloroquine beginning at 5 weeks of age. Cytoxan is administered at 50 mg/kg i.p. every 10 days. A serum sample is taken immediately before the beginning of treatment to monitor changes in autoreactive antibodies. Subsequently, serum samples are collected approximately monthly and analyzed for anti-dsDNA by ELISA after 1:500 dilution. Body weights and urine samples are taken at the same interval, and proteinuria is assessed by ChemStrips. Anti-nuclear antibodies (ANA) are assessed using commercially available HEp2 slide kits, with serum diluted to 1:100 in kit buffer. ANA scores are read blinded[1]. |
References: [1]. Lamphier M, et al. Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol. 2014 Mar;85(3):429-40. | |
| Cas No. | 1219925-73-1 | SDF | |
| Canonical SMILES | C1(C2=CC=C(OCCCN3CCCC3)C=C2)=NC4=CC=C(OCCCN5CCCC5)C=C4O1 | ||
| Formula | C27H35N3O3 | M.Wt | 449.59 |
| Solubility | DMSO : 8.33 mg/mL (18.53 mM; ultrasonic and warming and heat to 60°C) | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 2.2242 mL | 11.1212 mL | 22.2425 mL |
| 5 mM | 0.4448 mL | 2.2242 mL | 4.4485 mL |
| 10 mM | 0.2224 mL | 1.1121 mL | 2.2242 mL |
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 2 reference(s) in Google Scholar.)
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