| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| Other Sizes |
| Targets |
TLR7 (IC50 = 0.7 ± 0.2 nM in HEK293 NF-κB reporter assay) [1]
TLR8 (IC50 = 3.2 ± 1.2 nM in HEK293 NF-κB reporter assay) [1] TLR9 (IC50 = 350 ± 240 nM in HEK293 NF-κB reporter assay) [1] TLR3 (IC50 >10,000 nM) [1] TLR4 (IC50 >10,000 nM) [1] |
|---|---|
| ln Vitro |
In HEK293 NF-κB reporter assays: BMS-905 inhibited TLR7 with IC50 = 0.7 ± 0.2 nM, TLR8 with IC50 = 3.2 ± 1.2 nM, and TLR9 with IC50 = 350 ± 240 nM; selectivity for TLR7 over TLR9 was 500-fold, and for TLR8 over TLR9 was approximately 110-fold. No inhibition of TLR3 or TLR4 (IC50 >10,000 nM). [1]
In human peripheral blood mononuclear cell (hPBMC) IL-6 production assay: TLR7 IC50 = 1.0 ± 1.4 nM, TLR9 IC50 = 560 ± 270 nM. [1] In human whole blood IL-6 production assay: TLR8 IC50 = 4.2 ± 3.5 nM, TLR9 IC50 = 2000 ± 960 nM. [1] In mouse whole blood IL-6 production assay: TLR7 IC50 = 0.3 ± 0.2 nM, TLR9 IC50 >5000 nM. [1] Plasma protein binding free fractions: human 9%, rat 11%, mouse 5%. [1] |
| ln Vivo |
In TLR7 agonist (Gardiquimod) challenge mouse model: oral administration of BMS-905 at doses of 50 μg/kg, 150 μg/kg, 500 μg/kg, 1.5 mg/kg, and 5 mg/kg (30 min prior to agonist challenge) dose-dependently suppressed IL-6 production. Greater than 50% inhibition at 50 μg/kg and complete suppression at 500 μg/kg. [1]
In TLR9 agonist (ODN1585) challenge mouse model: BMS-905 at doses up to 30 mg/kg showed minimal impact on TLR9-induced cytokine elevation, consistent with selective TLR7 inhibition in mouse. [1] In MRL/lpr mouse model of systemic lupus erythematosus (male mice aged 12-14 weeks, randomized based on anti-dsDNA antibody titer and uNGAL level): once daily oral doses of BMS-905 at 0.1, 1, 5, 20 mg/kg for 8 weeks dose-dependently reduced disease parameters. Proteinuria and uNGAL were inhibited at the lowest dose (0.1 mg/kg/day) with maximal or near-maximal inhibition at 1.0 mg/kg/day, comparable or superior to prednisolone (10 mg/kg). Anti-Sm/RNP autoantibody titers were maximally inhibited at doses ≥1.0 mg/kg. Anti-dsDNA antibody titers were reduced only at 20 mg/kg. Relative spleen weight was reduced maximally at ≥1.0 mg/kg (51% reduction vs 88% for prednisolone). Body weight was not decreased by any dose of BMS-905 (prednisolone caused body weight loss). Treatment was well tolerated across all dose levels. [1] |
| Cell Assay |
HEK293 cell reporter assays for TLR antagonism: HEK293 cells stably expressing human TLR7, TLR8, or TLR9 along with NF-κB-luciferase reporter were used. Cells were incubated with test compounds and then stimulated with TLR agonists. Luciferase activity was measured to determine IC50 values. [1]
Human peripheral blood mononuclear cell (hPBMC) IL-6 assay: PBMCs were isolated from human blood, pre-incubated with compound, then stimulated with TLR7 or TLR9 agonists. IL-6 levels in supernatant were measured. [1] Human whole blood IL-6 assay: Human whole blood was pre-incubated with compound, then stimulated with TLR8 or TLR9 agonists. IL-6 production was measured. [1] Mouse whole blood IL-6 assay: Mouse whole blood was pre-incubated with compound, then stimulated with TLR7 or TLR9 agonists. IL-6 production was measured. [1] |
| Animal Protocol |
For TLR7 agonist challenge PD study: Male C57BL mice (n=8 per group) were treated with a single oral dose of BMS-905 (50 μg/kg, 150 μg/kg, 500 μg/kg, 1.5 mg/kg, 5 mg/kg) or vehicle. After 30 min, mice were challenged with TLR7 agonist Gardiquimod (dose not specified). Blood samples were collected 90-120 min post-challenge, and IL-6 levels were measured. [1]
For TLR9 agonist challenge PD study: Similar protocol using TLR9 agonist ODN1585. [1] For MRL/lpr mouse efficacy study: Male MRL/lpr mice aged 12-14 weeks were randomized based on anti-dsDNA antibody titer and urinary neutrophil gelatinase-associated lipocalin (uNGAL) level. Mice (n=12 per group) received once daily oral doses of BMS-905 (0.1, 1, 5, 20 mg/kg), prednisolone (10 mg/kg), or vehicle for 8 weeks. Formulation: for IV, 70/30 PEG400/water; for PO, 80/20 PEG400/200 mM citrate buffer (pH 3.0). Parameters measured: proteinuria, uNGAL, relative spleen weight, anti-Sm/RNP antibody titers, anti-dsDNA antibody titers, body weight. [1] |
| ADME/Pharmacokinetics |
Mouse blood pharmacokinetics after oral and intravenous administration: IV dose 5 mg/kg (70/30 PEG400/water), PO dose 15 mg/kg (80/20 PEG400/200 mM citrate buffer pH 3.0). Parameters: Tmax = 5 h, Cmax = 255 nM, C24h = 22 nM, AUClast (IV) = 1583 nM·h, AUClast (PO) = 2773 nM·h, Cl = 146 (mL/min)/kg, Vss = 113 L/kg, T1/2 = 9 h, oral bioavailability F = 58%. [1]
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| Toxicity/Toxicokinetics |
Plasma protein binding free fractions: human 9%, rat 11%, mouse 5% (no toxicity data reported). [1]
|
| References | |
| Additional Infomation |
BMS-905 is a dual TLR7/8 antagonist developed for treatment of autoimmune disorders such as lupus, psoriasis, and arthritis where aberrant activation of TLR7/8 pathways occurs due to recognition of self-RNA. X-ray cocrystal structure of BMS-905 with human TLR8 ECD (PDB: 7RC9) shows a 2:2 ratio with dimeric TLR8, with the protonated piperidine forming a salt bridge with Glu-427, indole NH engaging the amide carbonyl of Phe-494, and pyridine nitrogen interacting with Gly-351 in a monodentate fashion while the methyl groups at C2'/C6' orient the pyridine in a π-stacking hydrophobic pocket. The compound demonstrated good efficacy in MRL/lpr mouse model of lupus, supporting further development for autoimmune diseases. [1]
|
| Molecular Formula |
C23H29N3
|
|---|---|
| Molecular Weight |
347.4965
|
| Exact Mass |
347.24
|
| Elemental Analysis |
C, 79.50; H, 8.41; N, 12.09
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| CAS # |
2205846-49-5
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| PubChem CID |
134329228
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| Appearance |
White to off-white solid powder
|
| LogP |
4.7
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
3
|
| Heavy Atom Count |
26
|
| Complexity |
448
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC1=CC(=CC(=N1)C)C2=C(C3=C(N2)C=CC(=C3)C4CCNCC4)C(C)C
|
| InChi Key |
XSXCQWXAFRASGU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H29N3/c1-14(2)22-20-13-18(17-7-9-24-10-8-17)5-6-21(20)26-23(22)19-11-15(3)25-16(4)12-19/h5-6,11-14,17,24,26H,7-10H2,1-4H3
|
| Chemical Name |
2-(2,6-dimethylpyridin-4-yl)-5-piperidin-4-yl-3-propan-2-yl-1H-indole
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| Synonyms |
BMS 905; BMS-905; BMS905;
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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 : ~12.5 mg/mL (~35.97 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (3.60 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 12.5 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: ≥ 1.25 mg/mL (3.60 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 12.5 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: ≥ 1.25 mg/mL (3.60 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 | 2.8777 mL | 14.3885 mL | 28.7770 mL | |
| 5 mM | 0.5755 mL | 2.8777 mL | 5.7554 mL | |
| 10 mM | 0.2878 mL | 1.4388 mL | 2.8777 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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