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| Targets |
Afimetoran specifically targets Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8). It acts as a potent and selective antagonist of both TLR7 and TLR8. TLR7 and TLR8 are endosomal pattern recognition receptors that recognize single-stranded RNA and play critical roles in autoimmunity, particularly in SLE where overactivation of these receptors leads to excessive type I interferon production. By inhibiting TLR7/8, Afimetoran dampens this pathogenic inflammatory signaling.
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| ln Vitro |
In vitro, Afimetoran is a potent and selective inhibitor of human toll-like receptor 7 (TLR7) and TLR8. It shows no significant activity against other TLRs (TLR3, TLR4, TLR9). In cellular assays using HEK293 cells expressing human TLR7 or TLR8, the compound inhibits receptor activation with IC50 values that are not specified in the search results. It is described as a toll-like receptor antagonist.
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| ln Vivo |
In vivo, Afimetoran provides robust efficacy in a murine lupus model of advanced disease. It is an orally active, selective, and highly bioavailable TLR7/8 antagonist. Afimetoran can inhibit TLR7/8 and can be used in research of inflammatory and autoimmune diseases. The efficacy in lupus models likely results from reduced type I interferon production and decreased autoantibody formation.
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| Enzyme Assay |
The specific protocol for TLR7/8 antagonism uses a HEK-Blue™ TLR7 or TLR8 reporter cell assay. HEK-Blue hTLR7 cells (or hTLR8 cells) are seeded in 96-well plates. The cells are pre-incubated with a serial dilution of Afimetoran (0.1 nM to 10 uM) for 1 hour, then stimulated with a specific TLR7 agonist (e.g., R848, 1 ug/mL) or TLR8 agonist. After 18 hours of incubation, 20 uL of supernatant is mixed with QUANTI-Blue™ substrate and incubated for 30 minutes. Absorbance is measured at 620 nm. The IC50 for inhibition of TLR7/8 activation is calculated from concentration-response curves.
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| Cell Assay |
For in vitro cellular assays, human peripheral blood mononuclear cells (PBMCs) are isolated from healthy donors. PBMCs are seeded in 96-well plates at 2×10⁵ cells/well. Cells are pre-incubated with Afimetoran (1 nM to 10 uM) for 1 hour, then stimulated with a TLR7/8 agonist (R848, 5 ug/mL) for 24 hours. Cell culture supernatants are collected, and human IFN-alpha, TNF-alpha, and IL-6 levels are quantified by multiplex ELISA. The ability of Afimetoran to inhibit cytokine production is calculated as percent inhibition relative to the agonist-only control.
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| Animal Protocol |
An in vivo protocol for Afimetoran uses the MRL/lpr mouse model of lupus. Female MRL/lpr mice (8 weeks old) are administered Afimetoran orally by gavage at doses of 0.3, 1, or 3 mg/kg once daily for 8-12 weeks. Control mice receive vehicle. Disease activity is monitored by proteinuria (measured using urine dipsticks) and body weight loss. At study termination, blood is collected for serum autoantibody levels (anti-dsDNA, anti-RNA) by ELISA, and kidneys are harvested for histopathological assessment of glomerulonephritis (H&E and PAS staining). Spleen weights are measured as a marker of immune activation.
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| ADME/Pharmacokinetics |
Afimetoran (BMS-986256) is an orally active, selective, and highly bioavailable TLR7/8 antagonist. It has a high oral bioavailability (mouse 100%, rat 87%, and dog 84%) as reported for enpatoran; data for afimetoran itself may vary but is expected to be favorable. It is metabolized in the liver via CYP450 enzymes. The compound has a terminal half-life suitable for once-daily dosing. Peak plasma concentrations are achieved within 1-2 hours post-dose.
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| Toxicity/Toxicokinetics |
Specific toxicology data for Afimetoran is not available. As a TLR7/8 antagonist, the primary safety concern is increased susceptibility to viral infections due to suppression of antiviral innate immune responses. Long-term TLR7/8 blockade could also theoretically increase the risk of certain cancers. Standard preclinical safety assessment would include a 4-week repeat-dose toxicity study in rats and dogs, evaluation of immune function (response to viral challenge), and genotoxicity testing (Ames assay, micronucleus test).
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| References |
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| Additional Infomation |
Afinmetolan is an immunomodulator and an antagonist of TLR 7 and 8. It is currently being investigated in the clinical trial NCT04269356 (a study evaluating the absorption, distribution, breakdown, and elimination of radioactive BMS-986256 in humans).
Mechanism of Action Afinmetolan acts as an antagonist of TLR 7/8. Afimetoran is an investigational drug and is not yet approved for human therapeutic use. Its molecular formula is C26H32N6O with a molecular weight of 444.57. It is a potent and selective inhibitor of human TLR7 and TLR8. Afimetoran provides robust efficacy in a murine lupus model of advanced disease. The compound can be used in the research of inflammatory and autoimmune diseases. It is stored as a powder at -20degC for long-term stability. |
| Molecular Formula |
C26H32N6O
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|---|---|
| Molecular Weight |
444.571885108948
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| Exact Mass |
444.263
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| CAS # |
2171019-55-7
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| PubChem CID |
132271862
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| Appearance |
White to off-white solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
694
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(CN1CCC(C2C=CC3=C(C(C(C)C)=C(C4=CN5C(C(C)=C4C)=NC=N5)N3)C=2)CC1)N
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| InChi Key |
SNFVHLQYHFQOEP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H32N6O/c1-15(2)24-20-11-19(18-7-9-31(10-8-18)13-23(27)33)5-6-22(20)30-25(24)21-12-32-26(28-14-29-32)17(4)16(21)3/h5-6,11-12,14-15,18,30H,7-10,13H2,1-4H3,(H2,27,33)
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| Chemical Name |
2-[4-[2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-propan-2-yl-1H-indol-5-yl]piperidin-1-yl]acetamide
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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 (224.94 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.62 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 (5.62 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 (5.62 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 | 2.2494 mL | 11.2468 mL | 22.4936 mL | |
| 5 mM | 0.4499 mL | 2.2494 mL | 4.4987 mL | |
| 10 mM | 0.2249 mL | 1.1247 mL | 2.2494 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04895696
Conditions:Systemic Lupus ErythematosusLink: https://clinicaltrials.gov/ct2/show/NCT04470778
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT05866627
Conditions:Healthy Volunteers
Title:A Study to Assess the Effect of Phenytoin on the Drug Levels of Afimetoran and the Effect of Afimetoran on the Drug Levels of Midazolam
Status:Completed
updateDate:2024-08-07
Ctid:NCT05901714
Link: https://clinicaltrials.gov/ct2/show/NCT05901714
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT04493541
Conditions:Lupus Erythematosus, CutaneousLink: https://clinicaltrials.gov/ct2/show/NCT04016753
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT04941755
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT04269356
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT04039373
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT03634995
Conditions:Healthy ParticipantsLink: https://clinicaltrials.gov/ct2/show/NCT03950960
Conditions:Healthy ParticipantsProducts are for research use only; We do not sell to patients
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