SAR-20347 is a novel and potent small molecule inhibitor with specificity for JAK1 and tyrosine kinase 2 (TYK2) over other JAK family members. In cellular assays, SAR-20347 dose dependently (1 nM-10 μM) inhibited JAK1- and/or TYK2-dependent signaling from the IL-12/IL-23, IL-22, and IFN-α receptors. In vivo, TYK2 mutant mice or treatment of wild-type mice with SAR-20347 significantly reduced IL-12-induced IFN-γ production and IL-22-dependent serum amyloid A to similar extents, indicating that, in these models, SAR-20347 is probably acting through inhibition of TYK2. In an imiquimod-induced psoriasis model, the administration of SAR-20347 led to a striking decrease in disease pathology, including reduced activation of keratinocytes and proinflammatory cytokine levels compared with both TYK2 mutant mice and wild-type controls. Taken together, these data indicate that targeting both JAK1- and TYK2-mediated cytokine signaling is more effective than TYK2 inhibition alone in reducing psoriasis pathogenesis.
Physicochemical Properties
| Molecular Formula | C21H18CLFN4O4 |
| Molecular Weight | 444.8434 |
| Exact Mass | 444.1 |
| CAS # | 1450881-55-6 |
| Related CAS # | 1450881-55-6; 1450881-50-6 |
| PubChem CID | 71727668 |
| Appearance | Light yellow to yellow solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 698.3±65.0 °C at 760 mmHg |
| Flash Point | 376.1±34.3 °C |
| Vapour Pressure | 0.0±2.2 mmHg at 25°C |
| Index of Refraction | 1.644 |
| LogP | 0.22 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 31 |
| Complexity | 645 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | HEDPDFHTQKEORT-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C21H18ClFN4O4/c22-14-2-1-3-15(23)16(14)19-26-17(18(24)28)20(31-19)25-13-6-4-12(5-7-13)21(29)27-8-10-30-11-9-27/h1-7,25H,8-11H2,(H2,24,28) |
| Chemical Name | 2-(2-Chloro-6-fluorophenyl)-5-[[4-(4-morpholinylcarbonyl)phenyl]amino]-4-oxazolecarboxamide |
| Synonyms | SAR-20347; SAR 20347; SAR20347 |
| 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 |
| 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 | When NK-92 cells are stimulated with IL-12, SAR-20347 potently suppresses the TYK2-dependent event of STAT4 phosphorylation, which is mediated by IL-12, with an IC50 of 126 nM. The selectivity of SAR-20347 is TYK2>JAK1>JAK2>JAK3. When SAR-20347 and IL-12 were added to the culture medium, the synthesis of IFN-γ was dose-dependently inhibited in the cells that produced no detectable amount of the protein. The generation of secreted embryonic alkaline phosphatase (SEAP) is inhibited dose-dependently by SAR-20347, with the highest inhibitory impact observed in these trials at 5 μM [1]. |
| ln Vivo | SAR-20347 suppresses TYK2 signaling in vivo, as demonstrated by its 91% inhibition of IFN-γ production in serum at 60 mg/kg when compared to mice administered with a vehicle. In line with gene expression data, SAR-20347 therapy dramatically decreased IL-17 production as determined by mean signal intensity [1]. |
| References |
[1]. Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis. J Immunol. 2014 Oct 1;193(7):3278-87. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~100 mg/mL (~224.80 mM) |
| 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2480 mL | 11.2400 mL | 22.4800 mL | |
| 5 mM | 0.4496 mL | 2.2480 mL | 4.4960 mL | |
| 10 mM | 0.2248 mL | 1.1240 mL | 2.2480 mL |