| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
| Targets |
BTK (IC50 = 0.7 nM)
Tolebrutinib targets Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase that plays a critical role in B cell receptor signaling, Fc receptor signaling, and Toll-like receptor signaling. BTK is involved in the activation, proliferation, and survival of B cells and other immune cells. By irreversibly inhibiting BTK, tolebrutinib blocks downstream signaling pathways, reducing the production of inflammatory cytokines and autoantibodies. The compound's ability to cross the blood-brain barrier allows it to target BTK in the central nervous system, where it can modulate microglial activation and neuroinflammation. Tolebrutinib's irreversible binding to BTK results in sustained inhibition, even after the compound is cleared from the circulation. |
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| ln Vitro |
PRN2246 inhibits both Fc receptor activation (IC50=166 and 9.6 nM for FcεR and FcγR) and BCR-mediated immune cell activation (IC50=10 nM) [2]. With an IC50 of 157 nM, PRN2246 targets small molecule FcγR activation via persistent port BTK [2].
In vitro, tolebrutinib demonstrates potent inhibition of BTK in Ramos B cells (IC50 = 0.4 nM) and HMC microglia cells (IC50 = 0.7 nM). The compound also decreases the number of CD69+ B cells in isolated mouse whole blood with an IC50 of 200 nM. Tolebrutinib's irreversible binding to BTK results in sustained inhibition, even after the compound is cleared from the circulation. The compound's selectivity for BTK over other kinases contributes to its favorable safety profile. |
| ln Vivo |
PRN2246 (1-5 mg/kg; po, qd, for 28 days) exhibits dose-induced protection in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE) model [2].
In vivo, tolebrutinib has demonstrated efficacy in preclinical models of multiple sclerosis and other neuroinflammatory diseases. The compound's CNS-penetrant properties allow it to target BTK in the central nervous system, reducing neuroinflammation and demyelination. Tolebrutinib has been evaluated in clinical trials for multiple sclerosis, with promising results in reducing disease activity and slowing disease progression. The compound's irreversible BTK inhibition provides sustained pharmacodynamic effects. |
| Enzyme Assay |
Tolebrutinib's inhibition of BTK is assessed using biochemical and cell-based assays. In biochemical assays, recombinant BTK is incubated with the test compound, ATP, and a peptide substrate; phosphorylation of the substrate is detected using HTRF or luminescence-based methods. In cell-based assays, Ramos B cells or HMC microglia cells are treated with varying concentrations of tolebrutinib; BTK phosphorylation is assessed by Western blot using phospho-specific antibodies; B cell activation (CD69 expression) is assessed by flow cytometry. IC50 values are calculated from dose-response curves. These assays provide quantitative information on the potency of tolebrutinib.
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| Cell Assay |
Tolebrutinib is tested on cultured B cells, microglia cells, and other immune cells. Cells are treated with varying concentrations of tolebrutinib; BTK phosphorylation is assessed by Western blot; B cell activation and proliferation are assessed by flow cytometry; cytokine production is measured by ELISA; microglial activation is assessed by measuring inflammatory cytokine production and phagocytic activity. These cell-based assays demonstrate the mechanism of action and immunomodulatory activity of tolebrutinib.
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| Animal Protocol |
Tolebrutinib has been evaluated in animal models of multiple sclerosis and other neuroinflammatory diseases. In experimental autoimmune encephalomyelitis (EAE) models, tolebrutinib reduces disease severity, neuroinflammation, and demyelination. The compound's CNS-penetrant properties are confirmed by measuring drug concentrations in brain tissue. Tolebrutinib has also been evaluated in clinical trials for multiple sclerosis, including Phase 2 and Phase 3 trials for relapsing and progressive forms of MS.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of tolebrutinib have been conducted in preclinical species and humans. Tolebrutinib is orally active, with good oral bioavailability. The compound's ability to cross the blood-brain barrier is a key feature of its pharmacokinetic profile, allowing it to reach therapeutic concentrations in the central nervous system. Tolebrutinib's pharmacokinetic properties support once-daily oral dosing.
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| Toxicity/Toxicokinetics |
In clinical trials, tolebrutinib has been generally well-tolerated. Common adverse effects include infections, gastrointestinal disturbances, and headache. The safety profile of tolebrutinib is consistent with that of other BTK inhibitors. Serious adverse events are uncommon. Tolebrutinib's CNS-penetrant properties may contribute to its efficacy in progressive forms of MS.
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| References |
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| Additional Infomation |
Tolebrutinib is a small-molecule Bruton's tyrosine kinase (BTK) inhibitor with high oral bioavailability, blood-brain barrier penetration, and selective activity, possessing potential immunomodulatory and anti-inflammatory activities. After oral administration, Tolebrutinib crosses the blood-brain barrier and inhibits BTK activity in the peripheral and central nervous systems (CNS). This prevents activation of the B cell antigen receptor (BCR) signaling pathway, thereby suppressing immune activation and inflammatory responses. Inhibition of BTK activity also blocks inflammatory signaling in microglia of the CNS, thereby suppressing immune activation, neuroinflammation, and neurodegeneration. BTK is a cytoplasmic tyrosine kinase belonging to the Tec kinase family, playing a crucial role in the development, activation, signaling, proliferation, and survival of B lymphocytes. In addition to B cells, BTK is also expressed in innate immune cells such as macrophages and microglia, playing a vital role in regulating inflammatory signaling in microglia.
Tolebrutinib (SAR442168, PRN2246) is a potent, selective, orally active, irreversible BTK inhibitor with the ability to cross the blood-brain barrier. The compound has IC50 values of 0.4 nM in Ramos B cells and 0.7 nM in HMC microglia cells. Tolebrutinib is being developed for the treatment of multiple sclerosis, particularly secondary progressive multiple sclerosis. The compound's CNS-penetrant properties allow it to target BTK in the central nervous system, reducing neuroinflammation and demyelination. Tolebrutinib represents a promising new therapy for MS, with the potential to slow disease progression and improve neurological outcomes in both relapsing and progressive forms of the disease. |
| Molecular Formula |
C26H25N5O3
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|---|---|
| Molecular Weight |
455.5084
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| Exact Mass |
455.195
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| CAS # |
1971920-73-6
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| PubChem CID |
124111565
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
644.4±65.0 °C at 760 mmHg
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| Flash Point |
343.5±34.3 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.680
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| LogP |
1.76
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
749
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C=CC(=O)N1CCC[C@H](C1)N2C3=C(C(=NC=C3)N)N(C2=O)C4=CC=C(C=C4)OC5=CC=CC=C5
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| InChi Key |
KOEUOFPEZFUWRF-LJQANCHMSA-N
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| InChi Code |
InChI=1S/C26H25N5O3/c1-2-23(32)29-16-6-7-19(17-29)30-22-14-15-28-25(27)24(22)31(26(30)33)18-10-12-21(13-11-18)34-20-8-4-3-5-9-20/h2-5,8-15,19H,1,6-7,16-17H2,(H2,27,28)/t19-/m1/s1
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| Chemical Name |
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one
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| Synonyms |
Tolebrutinib; 1971920-73-6; PRN2246; SAR442168; Tolebrutinib [INN];
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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 (~219.53 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.49 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 (5.49 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 (5.49 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 | 2.1953 mL | 10.9767 mL | 21.9534 mL | |
| 5 mM | 0.4391 mL | 2.1953 mL | 4.3907 mL | |
| 10 mM | 0.2195 mL | 1.0977 mL | 2.1953 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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