Description
Baricitinib (1187594-09-7), approved by the FDA for two inflammatory disorders, rheumatoid arthritis and alopecia areata, selectively inhibits Janus kinase 1 (IC50?= 5.9 nM) and 2 (5.7 nM), over 3 (0.56 μM).1?It thereby blocks JAK/STAT signaling, reducing cytokine release and suppressing the innate and adaptive immune systems.1,2?Was recently shown to significantly improve COVID-19 symptoms in a preliminary human trial, presumably through suppression of the cytokine release syndrome (“cytokine storm”) induced by SARS-CoV-2 infection.3
Definition
ChEBI: Baricitinib is a pyrrolopyrimidine that is 7H-pyrrolo[2,3-d]pyrimidine substituted by a 1-[3-(cyanomethyl)-1-(ethanesulfonyl)azetidin-3-yl]-1H-pyrazol-4-yl group at position 5. It is an FDA approved selective Janus Kinase 1 and 2 (JAK1 and JAK2) inhibitor used for the treatment of rheumatoid arthritis. It has a role as an antirheumatic drug, an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, an anti-inflammatory agent, an immunosuppressive agent and an antiviral agent. It is a pyrrolopyrimidine, a member of pyrazoles, a member of azetidines, a sulfonamide and a nitrile.
Synthesis
Barectinib intermediate 3 (4-(1-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine) was used as a raw material, which was suspended in a solvent mixture of methanol (MeOH, 5 mL) and tetrahydrofuran (THF, 20 mL). To this suspension was added 1 M aqueous sodium hydroxide (NaOH, 2.3 mL, 2.3 mmol, 1 equiv) and methyl pivalate (20,1.0 g, 2.06 mmol). The reaction mixture was stirred at room temperature for 2-3 hours until HPLC monitoring showed that the reaction was complete. Subsequently, the reaction was quenched with 10 mL of water and 0.2 mL of aqueous 1N HCl and the pH was adjusted to 7-7.5. The mixture was continued to be stirred at room temperature for 30 min, and then the precipitated solid was collected by filtration. The solid was washed with a solvent mixture of acetonitrile and water (2:3 v/v, ca. 4 mL) and dried under vacuum at 40-45°C for 24 h to afford the crude product 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14,658 mg, Theoretical Yield 765 mg, 86% yield) was an off-white solid. The product was identified as being consistent with the material prepared by Method A. The 1H NMR (DMSO-d6, 300 MHz) data of crude product 14 were as follows: δ12.15 (s, 1H), 8.94 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.63 (d, 1H), 7.09 (d, 1H), 4.62 (d, 2H), 4.25 (d, 2H), 3.71 (s 2H), 3.24 (q, 2H), 1.26 (t, 3H) ppm. molecular formula C16H17N7O2S (molecular weight 371.42), LCMS (EI) m/e 372 (M++H).
Enzyme inhibitor
This selective, ATP-competitive protein kinase inhibitor (FW = 371.42 g/mol; CAS 1187594-09-7; Solubility: 70 mg/mL DMSO, <1 mg/mL H2O), also known by its code names LY3009104 and INCB028050 as well as its systematic name 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]-pyrimidin-4-yl)- 1H-pyrazol-1-yl]-3-azetidineacetonitrile, targets JAK1 and JAK2, with respective IC50 values of 5.9 nM and 5.7 nM, showing little effect on JAK3 (IC50 = 560 nM). In cell-based assays, INCB028050 proved to be a potent inhibitor of JAK signaling and function. Primary Mode of Inhibitory Action: Janus kinases JAK1, JAK2, JAK3, and the related enzyme TYK2 are critical components of signaling mechanisms used by many cytokines and growth factors, including several that are elevated in patients with RA. Cytokines such as interleukin-6, -12 and -23 and both type 1 and type 2 interferons signal through these pathways. JAK-dependent cytokines have been implicated in the pathogenesis of inflammatory and autoimmune diseases, suggesting that JAK inhibitors may be useful for the treatment of a broad range of inflammatory conditions. At concentrations <50 nM, baricitinib inhibits intracellular signaling of multiple proinflammatory cytokines including IL-6 and IL-23. Significant efficacy, as assessed by improvements in clinical, histologic and radiographic signs of disease, was achieved in a rat adjuvant arthritis model with baricitinib providing partial and/or periodic inhibition of JAK1/JAK2 and no inhibition of JAK3. Such findings suggest that fractional inhibition of JAK1 and JAK2 may be sufficient for significant pharmacological activity in autoimmune diseases, such as rheumatoid arthritis. A related JAK inhibitor, Tofacitinib, is approved in the U.S. for the treatment of RA. Target(s): Baricitinib shows moderate (~10x) selectivity against Tyk2 (IC50 = 53 nM) and marked selectivity over the unrelated c-Met (IC50 > 10,000 nM) and Chk2 (IC50 > 1,000 nM) kinases as well as ~100x higher IC50 values against Abl, Akt1, AurA, AurB, CDC2, CDK2, CDK4, CHK2, c-kit, EGFR, EphB4, ERK1, ERK2, FLT-1, HER2, IGF1R, IKKα, IKKβ, JNK1, Lck, MEK1, p38α, p70S6K, PKA, PKCα, Src, and ZAP70.
Metabolism
Baricitinib is hepatically metabolism by CYP3A4, <10%
of the dose identified as undergoing biotransformation.
No metabolites were detected in plasma.
In a clinical pharmacology study, baricitinib was excreted
mainly as the unchanged active substance in urine (69%)
and faeces (15%) and only 4 minor oxidative metabolites
were identified (3 in urine; 1 in faeces) constituting
approximately 5% and 1% of the dose, respectively
![(4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate](/CAS/20200331/GIF/1187595-90-9.gif)
