Baricitinib

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Cat Number

API1187594097

CAS Number

1187594-09-7

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CAS Number

1187594-09-7

EINECS

691-421-4

Storage

Store at -20℃

Synonyms

INCB28050; LY3009104; 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile; 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-azetidineacetonitrile

Molecular Formula

C16H17N7O2S

Molecular Weight

371.4

Smiles

CCS(=O)(=O)N1CC(C1)(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3

Appearance

White to off-white solid

Melting Point

193°C

Boiling Point

~707.2° C at 760 mmHg

General Description

Baricitinib is a pyrrolopyrimidine derivative in which the 7H-pyrrolo[2,3-d]pyrimidine core is substituted at position 5 with a 1-[3-(cyanomethyl)-1-(ethanesulfonyl)azetidin-3-yl]-1H-pyrazol-4-yl moiety. As an FDA-approved selective Janus Kinase 1 and 2 (JAK1 and JAK2) inhibitor, it is indicated for the treatment of rheumatoid arthritis.

Mechanism of Action

Baricitinib functions as a Janus kinase (JAK) inhibitor. These JAK enzymes are tyrosine kinases crucial for pro-inflammatory signaling pathways. Excessive JAK activity has been associated with autoimmune conditions like rheumatoid arthritis. Through its inhibition of JAK1 and JAK2, baricitinib reduces inflammation and immune responses mediated by JAK signaling pathways.

Application

Baricitinib was first approved by the European Commission (EC) in February 2017 for the treatment of rheumatoid arthritis in adults. Approval was later expanded by the EC to include the treatment of atopic dermatitis, becoming the first JAK inhibitor approved in Europe for this indication. The U.S. Food and Drug Administration (FDA) approved baricitinib for the treatment of rheumatoid arthritis in 2018. In the wake of the COVID-19 pandemic, baricitinib was granted emergency use authorization (EUA) in combination with remdesivir by the FDA in November 2020. Baricitinib was approved by the FDA for the treatment of COVID-19 in May 2022.

Cytokine signalling through JAKs is also important for osteoclast formation. Osteoblasts tightly control osteoclastogenesis through expression of the cytokines IL-6, IL-11, leukaemia inhibitory factor (LIF) and receptor activator of nuclear factor κ-light-chain-enhancer of activated B cells ligand (RANKL). In vitro experiments with murine osteoclasts and osteoblasts have shown that baricitinib exerts minimal direct action on osteoclasts but inhibits their formation by suppressing 1,25-dihydroxyvitamin D3 and prostaglandin E2-induced secretion of IL-6, IL-11 and LIF and expression of RANKL from osteoblasts. This is via the gp130/JAK signalling pathway, which is JAK1- and JAK2-dependent. Fibroblast-like synoviocytes have been implicated in RA pathogenesis, and biochemical studies have shown that baricitinib inhibits IFNγ-induced activation of focal adhesion kinase (FAK-Y925), an enzyme important in the migration of fibroblast-like synoviocytes. Baricitinib's inhibition of osteoblast RANKL expression and fibroblast-like synoviocyte migration may, in part, underlie its ability to prevent inflammation and joint damage.

References

Choy E H S, et al. The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib. Clinical and experimental rheumatology. 2019, 37(4): 694-407.

Baricitinib (BTB) is an orally administered Janus kinase inhibitor used for the treatment of rheumatoid arthritis and has been recently approved for treatment of COVID-19. It was loaded into four stearin-PLGA hybrid nanoparticles (B-PLN1-4) using single-step nanoprecipitation and characterized for their physicochemical properties such as particle size, zeta potential, PDI, entrapment efficiency (EE), and drug loading (DL). The B-PLN4 with particle size 272±7.6 nm, PDI 0.225, zeta potential -36.5±3.1 mV, EE 71.6±1.5%, and DL 2.87±0.42% was selected as the best formulation and was further subjected to evaluation of its morphology, in vitro release and in vivo pharmacokinetics in rats. Pharmacokinetic study showed 2.92-fold improvement in the bioavailability of B-PLN4 over pure BTB suspension. These results indicate the potential of lipid-polymer hybrid nanoparticles in improving the bioavailability of BTB and can serve as the scientific basis for future studies addressing the pharmacokinetic barriers.

Fig. 2 Baricitinib-loaded lipid-polymer hybrid nanoparticles. (Anwer M K, et al. 2021)

References

Anwer M K, et al. Development of sustained release baricitinib loaded lipid-polymer hybrid nanoparticles with improved oral bioavailability. Molecules. 2021, 27(1): 168.