Baricitinib phosphate salt Chemical Properties

storage temp. 

Store at -20°C

solubility 

insoluble in EtOH; insoluble in H2O; ≥172.6 mg/mL in DMSO

form 

White powder.

color 

White to yellow

InChIKey

FBPOWTFFUBBKBB-UHFFFAOYSA-N

SMILES

C(#N)CC1(N2C=C(C3=NC=NC4NC=CC=43)C=N2)CN(S(CC)(=O)=O)C1.P(O)(O)(O)=O

Baricitinib phosphate salt Usage And Synthesis

IC50 & Target

JAK2: 5.7 nM (IC50)  JAK1: 5.9 nM (IC50)   Tyk2: 53 nM (IC50)   JAK3: 560 nM (IC50) 

In Vivo

Baricitinib phosphate treatment, compares with vehicle, inhibits the increase in hind paw volumes during the 2 wk of treatment by 50% at a dose of 1 mg/kg and >95% at doses of 3 or 10 mg/kg. Because baseline paw volume measurements are taken on treatment day 0-in animals with significant signs of disease-it is possible to have >100% inhibition in animals showing marked improvement in swelling[1]. Baricitinib (0.7 mg/day) treated mice exhibits substantially reduced inflammation as assessed by H&E staining, reduced CD8 infiltration, and reduced MHC class I and class II expression when compared with vehicle-control treated mice. CD8+NKG2D+ cells, critical effectors of disease in murine and human alopecia areata (AA), are greatly diminished in Baricitinib treated mice compare with vehicle control treated mice.

Uses

Baricitinib phosphate salt is a JAK1 and JAK2 inhibitor and have been used as a promising treatment for rheumatoid arthritis.

Biological Activity

Baricitinib phosphate salt is a direct and indirect inhibition of the jaks has demonstrated rapid and sustained improvement in clinical measures of disease. baricitinib phosphate (incb 028050) is a selective jak1 and jak2 inhibitor.

Synthesis

General procedure for the synthesis of [1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl]acetonitrile phosphates from baricitinib: Barectinib (0.30 g, 0.8 mmol) was dissolved in boiling acetonitrile (7 ml), followed by the titrative addition, over a 30-minute period, of phosphoric acid ( 0.20 g, 2.1 equivalents, 85% aqueous solution) solution in methanol (1.2 ml). The reaction mixture was stirred at 68 °C for 1 h, then slowly cooled to room temperature and continued stirring overnight. The precipitate was collected by filtration and dried at 35 °C for 18 h at 200 mbar to give baricitinib phosphate of form C as a white powder (376 mg, 99.2% yield). The stoichiometric ratio was 1:1.14.

in vitro

In cell-based assays, Baricitinib phosphate proves to be a potent inhibitor of JAK signaling and function. In PBMCs, Baricitinib inhibits IL-6-stimulated phosphorylation of the canonical substrate STAT3 (pSTAT3) and subsequent production of the chemokine MCP-1 with IC50 values of 44 nM and 40 nM, respectively. In isolated naive T-cells, INCB028050 also inhibits pSTAT3 stimulated by IL-23 (IC50=20 nM). Importantly, this inhibition prevented the production of two pathogenic cytokines (IL-17 and IL-22) produced by Th17 cells-a subtype of helper T cells with demonstrable inflammatory and pathogenic properties-with an IC50 value of 50 nM. In stark contrast, the structurally similar but ineffective JAK1/2 inhibitors INCB027753 and INCB029843 has no significant effect in any of these assays systems when tested at concentrations up to 10 μM.

in vivo

significant efficacy was achieved in the rat adjuvant arthritis model with doses of baricitinib phosphate providing partial and/or periodic inhibition of jak1/jak2 and no inhibition of jak3. baricitinib phosphate was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse hematologic effects [2].

IC 50

JAK2: 5.7 nM (IC₅₀); JAK1: 5.9 nM (IC₅₀); Tyk2: 53 nM (IC₅₀); JAK3: 560 nM (IC₅₀)

References

[1] fridman js, scherle pa, collins r, burn tc, li y, li j, covington mb, thomas b, collier p, favata mf, wen x, shi j, mcgee r, haley pj, shepard s, rodgers jd, yeleswaram s, hollis g, newton rc, metcalf b, friedman sm, vaddi k. selective inhibition of jak1 and jak2 is efficacious in rodent models of arthritis: preclinical characterization of incb028050. j immunol. 2010;184(9):5298-307.

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