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AT791 (AT-791) is a novel and potent inhibitor of TLR7 and TLR9 with anti-inflammatory and immunomodulatory effects. It inhibits TLR7 and TLR9 with IC50 of 3.33 uM and 0.04 uM respectively.
| Targets |
TLR7 (IC50 = 3.33 μM); TLR9 (IC50 = 0.04 μM)
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|---|---|
| ln Vitro |
AT791 has been shown to be able to effectively suppress HEK:TLR9 cell DNA stimulation (IC50 = 0.04 μM), but R848 (IC50 = 3.33 μM) has a substantially weaker effect on HEK:TLR7 cell stimulation [1]. Due to their lipophilicity and weakly basic amino acid content, AT791 and E6446 are typical "lysosomal" molecules. These substances have IC50s between 1 and 10 μM and behave non-polarly at neutral pH [1]. are polarizing membranes and sexual; yet, in low pH vesicles, they get protonated and imprisoned (de Duve et al., 1974). With respect to the lysosomal compartment, they satisfy a higher degree of protonation than in the cytoplasm, as demonstrated by capillary polarization, which yielded pKas of 7.9 and 6.1 for AT791 and 8.6 and 6.5 for E6446 [1].
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| ln Vivo |
AT791 (20 mg/kg; po) can efficiently block the CpG1668 DNA-induced short-term increase of serum interleukin-6 in mice [1].
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| Enzyme Assay |
Inhibition of TLR9 and TLR7 Signaling by Small Molecule Ligands [1]
HEK293 cells expressing cloned human TLR9 and an NF-κB:luciferase reporter (HEK:TLR9 cells) were used to screen a compound library for small molecules that could suppress induction of NF-κB by stimulatory DNA (CpG2006). AT791 and E6446 (Fig. 1A) potently suppressed DNA stimulation of HEK:TLR9 cells, with IC50 values of 40 and 10 nM, respectively, but were significantly less effective at suppressing LPS endotoxin stimulation of HEK:TLR4 cells (Table 1) or R848 stimulation of HEK:TLR7 cells. |
| References | |
| Additional Infomation |
The discovery that circulating nucleic acid-containing complexes in the serum of patients with autoimmune lupus can stimulate B cells and plasma cell-like dendritic cells via Toll-like receptors 7 and 9 suggests that drugs that block these receptors may be a useful treatment option. We identified two compounds, AT791 {3-[4-(6-(3-(dimethylamino)propoxy)benzo[d]oxazol-2-yl)phenoxy]-N,N-dimethylpropyl-1-amine} and E6446 {6-[3-(pyrrolidone-1-yl)propoxy)-2-(4-(3-(pyrrolidone-1-yl)propoxy)phenyl]benzo[d]oxazol}, that inhibit the Toll-like receptor (TLR) 7 and TLR9 signaling pathways in multiple human and mouse cell types and suppress DNA-TLR9 interaction in vitro. When administered to mice, these compounds inhibited the mouse response to doses of cytidine phosphate guanidine (CpG) DNA stimulation, which stimulates TLR9. Long-term administration of E6446 in a spontaneous mouse lupus model slowed the production of circulating antinuclear antibodies and antagonized double-stranded DNA. The antibody titer had a slight effect, but no effect on other aspects was observed. Proteinuria or death. We found that the ability of AT791 and E6446 to inhibit TLR7 and TLR9 signaling depends on two properties: weak interaction with nucleic acids and high accumulation in the intracellular acidic compartments where TLR7 and TLR9 reside. The binding of these compounds to DNA prevents DNA-TLR9 interaction in vitro and modulates signaling in vivo. Our data also confirm previous reports that the same mechanism may explain the inhibitory effect of hydroxychloroquine (Plaquenil; Sanofi-Aventis, Bridgewater, NJ) on TLR7 and TLR9 signaling, a drug commonly used to treat lupus. Thus, the fact that structurally distinct classes of molecules can inhibit endosome TLRs through essentially the same mechanism suggests the existence of a universal mechanism for targeting this class of TLRs. [1]
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| Molecular Formula |
C23H31N3O3
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|---|---|
| Molecular Weight |
397.510545969009
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| Exact Mass |
397.236
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| Elemental Analysis |
C, 69.49; H, 7.86; N, 10.57; O, 12.07
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| CAS # |
1219962-49-8
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| PubChem CID |
45256283
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| Appearance |
White to off-white solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
29
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| Complexity |
455
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O(C1C=CC2=C(C=1)OC(C1C=CC(=CC=1)OCCCN(C)C)=N2)CCCN(C)C
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| InChi Key |
JKFYWFWUJUHSMZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H31N3O3/c1-25(2)13-5-15-27-19-9-7-18(8-10-19)23-24-21-12-11-20(17-22(21)29-23)28-16-6-14-26(3)4/h7-12,17H,5-6,13-16H2,1-4H3
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| Chemical Name |
3-[4-[6-[3-(dimethylamino)propoxy]-1,3-benzoxazol-2-yl]phenoxy]-N,N-dimethylpropan-1-amine
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| Synonyms |
AT791; 1219962-49-8; 3-(4-(6-(3-(Dimethylamino)propoxy)benzo[d]oxazol-2-yl)phenoxy)-N,N-dimethylpropan-1-amine; 3-[4-[6-[3-(dimethylamino)propoxy]-1,3-benzoxazol-2-yl]phenoxy]-N,N-dimethylpropan-1-amine; SCHEMBL12396693;
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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 |
| 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 (~251.57 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.29 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 (6.29 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 (6.29 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 | 2.5157 mL | 12.5783 mL | 25.1566 mL | |
| 5 mM | 0.5031 mL | 2.5157 mL | 5.0313 mL | |
| 10 mM | 0.2516 mL | 1.2578 mL | 2.5157 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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