E6446 dihydrochloride (E-6446 dihydrochloride)

E6446 dihydrochloride is a potent and orally acitve TLR7 and TLR9 antagonist, used in the research of deleterious inflammatory responses. E6446 dihydrochloride 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. 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. 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. 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. . 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. . 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.

Product information

CAS Number: 1345675-25-3

Molecular Weight: 522.51

Formula: C27H37Cl2N3O3

Chemical Name: 6-[3-(pyrrolidin-1-yl)propoxy]-2-{4-[3-(pyrrolidin-1-yl)propoxy]phenyl}-1,3-benzoxazole dihydrochloride

Smiles: Cl.Cl.C(CCN1CCCC1)OC1C=CC(=CC=1)C1=NC2=CC=C(C=C2O1)OCCCN1CCCC1

InChiKey: DQOUZINBHKWGGM-UHFFFAOYSA-N

InChi: InChI=1S/C27H35N3O3.2ClH/c1-2-14-29(13-1)17-5-19-31-23-9-7-22(8-10-23)27-28-25-12-11-24(21-26(25)33-27)32-20-6-18-30-15-3-4-16-30;;/h7-12,21H,1-6,13-20H2;2*1H

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

Products are for research use only. Not for human use.