Baricitinib

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

• Sicherheit

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

Baricitinib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  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

• Charakteristisch

  Primary targets: JAK1/2
  Class: non-receptor tyrosine kinase
  Treatment: rheumatoid arthritis
  Oral bioavailability = 79%
  Elimination half-life = 12.5 h
  Protein binding = 50%

• Verwenden

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

• 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.

• Clinical Use

  Janus kinase inhibitor:
  
  Treatment of moderate to severe active rheumatoid arthritis

• Enzyminhibitor

  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.

• target

  JAK2

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Avoid with other DMARDs due to increased immunosuppression.
  Use with care with other immunosuppressants.
  Antipsychotics: increased risk of agranulocytosis with clozapine - avoid.
  Live vaccines: avoid concomitant use

• Stoffwechsel

  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

• Lager

  Store at -20°C

• Einzelnachweise

  1) Fridman?et al.?(2010),?Selective Inhibition of JAK1 and JAK2 Is Efficacious in Rodent Models of Arthritis: Preclinical Characterization of INCB028050; J. Immunol. Biol.,?184?5298 2) Kubo?et al.?(2018),?Janus Kinase Inhibitor Baricitinib Modulates Human Innate and Adaptive Immune System; Front. Immunol.,?9?1510 3) Cantini?et al.?(2020),?Baricitinib Therapy in COVID-19: A Pilot Study on Safety and Clinical Impact; J. Infect.,?81?318

Baricitinib Upstream-Materialien And Downstream Produkte

Baricitinib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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