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.
Physicochemical Properties
| Molecular Formula | C25H29F2N7O4S | |
| Molecular Weight | 561.604070425034 | |
| Exact Mass | 561.196 | |
| CAS # | 2140301-96-6 | |
| Related CAS # | Brepocitinib;1883299-62-4 | |
| PubChem CID | 135087197 | |
| Appearance | White to off-white solid powder | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 11 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 39 | |
| Complexity | 815 | |
| Defined Atom Stereocenter Count | 1 | |
| 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 |
|
| InChi Key | FAKGOYNHHHOTEN-WTMFEIAXSA-N | |
| InChi Code | InChI=1S/C18H21F2N7O.C7H8O3S/c1-25-8-11(7-22-25)23-17-21-5-4-15(24-17)26-9-12-2-3-13(10-26)27(12)16(28)14-6-18(14,19)20;1-6-2-4-7(5-3-6)11(8,9)10/h4-5,7-8,12-14H,2-3,6,9-10H2,1H3,(H,21,23,24);2-5H,1H3,(H,8,9,10)/t12?,13?,14-;/m0./s1 | |
| Chemical Name |
|
|
| Synonyms |
|
|
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
|
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| 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]. |
| 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]. |
| 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]. 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. |
Solubility Data
| Solubility (In Vitro) |
|
|||
| 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. 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. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7806 mL | 8.9031 mL | 17.8063 mL | |
| 5 mM | 0.3561 mL | 1.7806 mL | 3.5613 mL | |
| 10 mM | 0.1781 mL | 0.8903 mL | 1.7806 mL |