WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 561151
CAS#: 1219925-73-1 (free base)
Description: E6446 is a TLR inhibitor. E6446 inhibits Toll-like receptor (TLR)7 and 9 signaling. E6446 works in a variety of human and mouse cell types and inhibits DNA-TLR9 interaction in vitro. When administered to mice, this compound suppress responses to challenge doses of cytidine-phosphate-guanidine (CpG)-containing DNA, which stimulates TLR9.
MedKoo Cat#: 561151
Name: E6446
CAS#: 1219925-73-1 (free base)
Chemical Formula: C27H35N3O3
Exact Mass: 449.2678
Molecular Weight: 449.595
Elemental Analysis: C, 72.13; H, 7.85; N, 9.35; O, 10.68
Related CAS #: 1345675-25-3 (HCl) 1219925-73-1 (free base)
Synonym: E6446; E 6446; E-6446
IUPAC/Chemical Name: 6-(3-Pyrrolidin-1-yl-propoxy)-2-[4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-benzooxazole
InChi Key: YMYJXFUPMPMETB-UHFFFAOYSA-N
InChi Code: InChI=1S/C27H35N3O3/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
SMILES Code: C1(C2=CC=C(OCCCN3CCCC3)C=C2)=NC4=CC=C(OCCCN5CCCC5)C=C4O1
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | E6446 is an inhibitor of Toll-like receptor (TLR) 7 and 9 signaling in a variety of human and mouse cell types and inhibits DNA-TLR9 interaction in vitro. |
| In vitro activity: | Measurement of ELAM-1–luciferase activity showed that E6446 specifically inhibited TLR9 activation with CpG ODN 2006, in the range of 0.01–0.03 μM. A 100-fold higher concentration (2–8 μM) of E6446 was required to inhibit TLR7/8 activated by the imidazoquinoline compound R848. Incubation of cells with even higher concentrations (30 μM) of E6446 was required to reduce 50% of TLR4 activation (Fig. 2A). Reference: Proc Natl Acad Sci U S A. 2011 Mar 1; 108(9): 3689–3694. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048158/ |
| In vivo activity: | E6446 treatment significantly reduced LV chamber size and improved cardiac function in TAC-operated mice. Reference: JACC Basic Transl Sci. 2019 Jun; 4(3): 348–363. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610159/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| Ethanol | 90.0 | 200.18 |
The following data is based on the product molecular weight 449.595 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Ueda H, Yamaguchi O, Taneike M, Akazawa Y, Wada-Kobayashi H, Sugihara R, Yorifuji H, Nakayama H, Omiya S, Murakawa T, Sakata Y, Otsu K. Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice. JACC Basic Transl Sci. 2019 May 22;4(3):348-363. doi: 10.1016/j.jacbts.2019.01.002. PMID: 31312759; PMCID: PMC6610159. 2. Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, Rose J, Zheng W, Ataíde MA, de Oliveira RB, Golenbock DT, Gazzinelli RT. 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. doi: 10.1073/pnas.1015406108. Epub 2011 Feb 8. PMID: 21303985; PMCID: PMC3048158. 3. Yoshida K, Abe K, Ishikawa M, Saku K, Shinoda-Sakamoto M, Ishikawa T, Watanabe T, Oka M, Sunagawa K, Tsutsui H. Inhibition of TLR9-NF-κB-mediated sterile inflammation improves pressure overload-induced right ventricular dysfunction in rats. Cardiovasc Res. 2019 Mar 1;115(3):658-668. doi: 10.1093/cvr/cvy209. PMID: 30239623. |
| In vitro protocol: | 1. Ueda H, Yamaguchi O, Taneike M, Akazawa Y, Wada-Kobayashi H, Sugihara R, Yorifuji H, Nakayama H, Omiya S, Murakawa T, Sakata Y, Otsu K. Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice. JACC Basic Transl Sci. 2019 May 22;4(3):348-363. doi: 10.1016/j.jacbts.2019.01.002. PMID: 31312759; PMCID: PMC6610159. 2. Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, Rose J, Zheng W, Ataíde MA, de Oliveira RB, Golenbock DT, Gazzinelli RT. 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. doi: 10.1073/pnas.1015406108. Epub 2011 Feb 8. PMID: 21303985; PMCID: PMC3048158. |
| In vivo protocol: | 1. Ueda H, Yamaguchi O, Taneike M, Akazawa Y, Wada-Kobayashi H, Sugihara R, Yorifuji H, Nakayama H, Omiya S, Murakawa T, Sakata Y, Otsu K. Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice. JACC Basic Transl Sci. 2019 May 22;4(3):348-363. doi: 10.1016/j.jacbts.2019.01.002. PMID: 31312759; PMCID: PMC6610159. 2. Yoshida K, Abe K, Ishikawa M, Saku K, Shinoda-Sakamoto M, Ishikawa T, Watanabe T, Oka M, Sunagawa K, Tsutsui H. Inhibition of TLR9-NF-κB-mediated sterile inflammation improves pressure overload-induced right ventricular dysfunction in rats. Cardiovasc Res. 2019 Mar 1;115(3):658-668. doi: 10.1093/cvr/cvy209. PMID: 30239623. |
1: Ishikawa T, Abe K, Takana-Ishikawa M, Yoshida K, Watanabe T, Imakiire S, Hosokawa K, Hirano M, Hirano K, Tsutsui H. Chronic Inhibition of Toll-Like Receptor 9 Ameliorates Pulmonary Hypertension in Rats. J Am Heart Assoc. 2021 Apr 6;10(7):e019247. doi: 10.1161/JAHA.120.019247. Epub 2021 Mar 31. PMID: 33787285; PMCID: PMC8174358.
2: Mohammadi O, Krieger D, Butt I, Danckers M. A Case of Delayed Diagnosis of Moyamoya Disease After Recurrent Strokes. Cureus. 2019 Dec 22;11(12):e6446. doi: 10.7759/cureus.6446. PMID: 32010532; PMCID: PMC6975246.
3: Ueda H, Yamaguchi O, Taneike M, Akazawa Y, Wada-Kobayashi H, Sugihara R, Yorifuji H, Nakayama H, Omiya S, Murakawa T, Sakata Y, Otsu K. Administration of a TLR9 Inhibitor Attenuates the Development and Progression of Heart Failure in Mice. JACC Basic Transl Sci. 2019 May 22;4(3):348-363. doi: 10.1016/j.jacbts.2019.01.002. PMID: 31312759; PMCID: PMC6610159.
4: Monteiro WP, Veiga JC, Silva AR, Carvalho CDS, Lanes ÉCM, Rico Y, Jaffé R. Everything you always wanted to know about gene flow in tropical landscapes (but were afraid to ask). PeerJ. 2019 Feb 13;7:e6446. doi: 10.7717/peerj.6446. PMID: 30783576; PMCID: PMC6377592.
5: Yoshida K, Abe K, Ishikawa M, Saku K, Shinoda-Sakamoto M, Ishikawa T, Watanabe T, Oka M, Sunagawa K, Tsutsui H. Inhibition of TLR9-NF-κB-mediated sterile inflammation improves pressure overload-induced right ventricular dysfunction in rats. Cardiovasc Res. 2019 Mar 1;115(3):658-668. doi: 10.1093/cvr/cvy209. PMID: 30239623.
6: Bell GD, Yang Y, Leung E, Krissansen GW. mRNA transfection by a Xentry- protamine cell-penetrating peptide is enhanced by TLR antagonist E6446. PLoS One. 2018 Jul 30;13(7):e0201464. doi: 10.1371/journal.pone.0201464. PMID: 30059522; PMCID: PMC6066245.
7: Yan L, Liu Y, He B, Liu J, Luo Z, Hao D. Clinical case-series report of traumatic cauda equina herniation: A pathological phenomena occurring with thoracolumbar and lumbar burst fractures. Medicine (Baltimore). 2017 Apr;96(14):e6446. doi: 10.1097/MD.0000000000006446. PMID: 28383409; PMCID: PMC5411193.
8: Dias AA, Silva CO, Santos JP, Batista-Silva LR, Acosta CC, Fontes AN, Pinheiro RO, Lara FA, Machado AM, Nery JA, Sarno EN, Pereira GM, Pessolani MC. DNA Sensing via TLR-9 Constitutes a Major Innate Immunity Pathway Activated during Erythema Nodosum Leprosum. J Immunol. 2016 Sep 1;197(5):1905-13. doi: 10.4049/jimmunol.1600042. Epub 2016 Jul 29. PMID: 27474073.
9: Maticorena-Quevedo J, Anduaga-Beramendi A, Beas R. Burnout syndrome among medical students in Mexico: considerations about its measurement with the Maslach Burnout Inventory. Medwave. 2016 May 17;16(4):e6446. English, Spanish. doi: 10.5867/medwave.2016.04.6446. PMID: 27218262.
10: Au HH, Cornilescu G, Mouzakis KD, Ren Q, Burke JE, Lee S, Butcher SE, Jan E. Global shape mimicry of tRNA within a viral internal ribosome entry site mediates translational reading frame selection. Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):E6446-55. doi: 10.1073/pnas.1512088112. Epub 2015 Nov 9. PMID: 26554019; PMCID: PMC4664324.
11: Lamphier M, Zheng W, Latz E, Spyvee M, Hansen H, Rose J, Genest M, Yang H, Shaffer C, Zhao Y, Shen Y, Liu C, Liu D, Mempel TR, Rowbottom C, Chow J, Twine NC, Yu M, Gusovsky F, Ishizaka ST. Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol. 2014 Mar;85(3):429-40. doi: 10.1124/mol.113.089821. Epub 2013 Dec 16. PMID: 24342772.
12: O'Dowd A. Serco admits it changed GPs' out of hours performance data 252 times. BMJ. 2012 Sep 24;345:e6446. doi: 10.1136/bmj.e6446. PMID: 23007627.
13: Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, Rose J, Zheng W, Ataíde MA, de Oliveira RB, Golenbock DT, Gazzinelli RT. 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. doi: 10.1073/pnas.1015406108. Epub 2011 Feb 8. PMID: 21303985; PMCID: PMC3048158.
14: De Iuliis GN, Newey RJ, King BV, Aitken RJ. Mobile phone radiation induces reactive oxygen species production and DNA damage in human spermatozoa in vitro. PLoS One. 2009 Jul 31;4(7):e6446. doi: 10.1371/journal.pone.0006446. Erratum in: PLoS One. 2013;8(3). doi:10.1371/annotation/9a8a0172-3850-4059-b852-72c330769c1b. PMID: 19649291; PMCID: PMC2714176.
