E6446 HCl | CAS#1345675-25-3 | TLR inhibitor

MedKoo Cat#: 555222 | Name: E6446 HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

E6446 is a synthetic antagonist of nucleic acid-sensing TLRs. , In vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446.

Chemical Structure

E6446 HCl

CAS#1345675-25-3 (HCl)

Theoretical Analysis

MedKoo Cat#: 555222

Name: E6446 HCl

CAS#: 1345675-25-3 (HCl)

Chemical Formula: C27H37Cl2N3O3

Exact Mass: 0.0000

Molecular Weight: 522.51

Elemental Analysis: C, 62.07; H, 7.14; Cl, 13.57; N, 8.04; O, 9.19

Price and Availability

Size	Price	Availability
50mg	USD 750.00	2 weeks
100mg	USD 1,250.00	2 Weeks
200mg	USD 2,250.00	2 weeks

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Related CAS #

1219925-73-1 (free base) 1345675-25-3 (HCl)

Synonym

E6446 HCl; E6446; E-6446; E6446 hydrochloride

IUPAC/Chemical Name

6-(3-pyrrolidin-1-ylpropoxy)-2-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-1,3-benzoxazole;dihydrochloride

InChi Key

DQOUZINBHKWGGM-UHFFFAOYSA-N

InChi Code

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

SMILES Code

[H]Cl.[H]Cl.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

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

E6446 dihydrochloride is a specific Toll-like receptor 9 inhibitor.

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	mg/mL	mM
Solubility
	DMSO	7.5	14.35
	DMF	20.0	38.28
	DMF:PBS (pH 7.2) (1:4)	0.2	0.38
	Ethanol	2.0	3.83
	Water	100.0	191.38

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 522.51 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:

In vivo protocol:

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.