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Purity: ≥98%
Brepocitinib (PF-06700841) tosylate, the tosylate salt of Brepocitinib, is a conformationally constrained piperazinyl-pyrimidine-based, Type 1 ATP site inhibitor of TYK2 and JAK1 kinases with IC50 values of 23 nM and 17 nM respectively. PF-06700841 is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868) as a potential therapeutic for the treatment of systemic lupus erythematosus and plaque psoriasis. Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies.
| ln Vitro |
Brepocitinib (Compound 23) potently inhibits TYK2/JAK2 mediated IL-12/pSTAT4 and IL-23/pSTAT3 (human whole blood (HWB) IC50s of 65 and 120 nM, respectively). Brepocitinib exhibits good activity against IL6/pStat1 in the CD3+ cellular subset (IC50 of 81 nM), but weaker inhibition of IL6/pSTAT3, likewise in the CD3+ cellular subset (IC50 of 641 nM). Brepocitinib also suppresses the JAK1/JAK3 driven γ-common chain cytokines, represented by IL-15/ pStat5 and IL-21/pSTAT3 with reasonable potency (HWB IC50s of 238 and 204 nM, respectively). Brepocitinib inhibits EPO/pSTAT5 (JAK2 homodimer) in HWB spiked with CD34+ progenitor cells (IC50 of 577 nM). IL10/pSTAT3 (TYK2 /JAK1) and IL27/pSTAT3 (JAK1/JAK2/TYK2) are likewise suppressed by Brepocitinib with IC50s of 305 nM and 86 nM, respectively[1].
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| ln Vivo |
The oral delivery of brepocitinib (Compound 23; 3–30 mg/kg) to female Lewis rats for seven days in a row considerably lowers the rise in paw volume in a dose-dependent manner. Animals given Brepocitinib were given the following plasma concentrations at peak (30 min) and trough (24 h) time intervals after the final dose: 3 mg/kg, 3.54 μM, 0.0221 μM; 10 mg/kg, 10.95 μM, 0.06 μM; and 30 mg/kg, 23.89 μM, 0.06 μM [1].
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| Animal Protocol |
Animal/Disease Models: Female Lewis rats with induced arthritis[1]
Doses: 3 mg/kg, 10 mg/kg, or 30 mg/kg Route of Administration: Oral administration; for 7 days Experimental Results: Increased in paw volume was Dramatically lower and dose-dependent. |
| References |
[1]. Fensome A, et al. Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700
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| Molecular Formula |
C25H29F2N7O4S
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| Molecular Weight |
561.61
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| CAS # |
2140301-96-6
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| Related CAS # |
Brepocitinib;1883299-62-4
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| SMILES |
S(C1C=CC(C)=CC=1)(=O)(=O)O.FC1(C[C@H]1C(N1[C@@H]2CN(C3C=CN=C(NC4C=NN(C)C=4)N=3)C[C@H]1CC2)=O)F
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| Chemical Name |
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.70 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 20.8 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: ≥ 2.08 mg/mL (3.70 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 20.8 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: ≥ 2.08 mg/mL (3.70 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 | 1.7806 mL | 8.9030 mL | 17.8060 mL | |
| 5 mM | 0.3561 mL | 1.7806 mL | 3.5612 mL | |
| 10 mM | 0.1781 mL | 0.8903 mL | 1.7806 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.
 J Med Chem.2018 Oct 11;61(19):8597-8612. |
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