Upadacitinib

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.

Upadacitinib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Upadacitinib is a JAK1 inhibitor (IC₅₀ = 47 nM). It is selective for JAK1 over JAK3 and tyrosine kinase 2 (Tyk2; IC₅₀s = 2,304 and 4,690 nM, respectively), as well as a panel of 83 additional kinases at 1 μM, but does inhibit JAK2, Rho-associated kinase I (ROCK1), and ROCK2 (IC₅₀s = 120, 920, and 430 nM, respectively). Upadacitinib decreases cytokine-induced STAT phosphorylation in a variety of human cells with IC₅₀ values ranging from 1.6 to 649 nM. It reduces M. tuberculosis-induced paw swelling and bone erosion in a rat model of arthritis when administered at doses of 1, 3, and 10 mg/kg twice per day for 17 days. Formulations containing upadacitinib have been used in the treatment of rheumatoid arthritis.

• Charakteristisch

  Class: non-receptor tyrosine kinase
  Treatment: psoriatic arthritis, rheumatoid arthritis
  Elimination half-life = 6–16 h
  Protein binding = 52%
  

• Verwenden

  Upadacitinib also known as ABT-494, is a potent and selective Janus kinase (JAK) 1 inhibitor  being developed for the treatment of several autoimmune disorders, Janus kinase inhibitors for rheumatoid arthritis. It is used to treat moderate to severely active rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis (a type of arthritis in the spine) with objective signs of swelling, moderate to severe ulcerative colitis, and moderate to severe Crohn's disease in patients who have taken other medicines (eg, methotrexate) that did not work well. It is also used to treat moderate to severe atopic dermatitis (eczema) in patients who have taken other medicines that did not work well and whose condition is not well controlled with other treatments or in patients who cannot tolerate these treatments.  It is also used to treatpsoriatic arthritis, axial SpA and Giant Cell Arteritis and Takayasu Arteritis.

• Trademarks

  Upadacitinib is marketed under the brand name RINVOQ for oral administration.

• Biologische Aktivität

  Upadacitinib is a potent, orally active and selective Janus kinase 1 (JAK1) inhibitor (IC50=43 nM). Upadacitinib displays approximately 74 fold selective for JAK1 over JAK2 (200 nM) in cellular assays dependent on specific, relevant cytokines. Upadacitinib can be used for several autoimmune disorders research. In vivo, Upadacitinib inhibited paw swelling and bone destruction in a rat model of arthritis.

• Mechanism of action

  The Janus kinases (JAKs) are a family of cytoplasmic tyrosine kinases whose function is to transduce cytokine-mediated signals via the JAK-STAT pathway. There are four JAK subtypes, each of which has overlapping receptor responsibilities. Inhibitors of this enzyme family (jakinibs) have shown efficacy in treating certain inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohn's disease. However, the first generation of these drugs, tofacitinib and ruxolitinib, lacked subtype selectivity, affecting JAK1/JAK3 and JAK1/JAK2 respectively. This has led to dose-limiting side effects in this otherwise promising class of drugs. Upadacitinib is a second generation Janus kinase inhibitor that is selective for the JAK1 subtype of this enzyme over the JAK2 (74-fold), JAK3 (58-fold) and tyrosine kinase 2 subtypes.

• Clinical Use

  Upadacitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). Upadacitinib may be used as monotherapy or in combination with methotrexate.

• Nebenwirkungen

  Common side effects are upper respiratory tract infections such as common cold and sinus infections (13.5% of patients in studies), nausea (3.5%), cough (2.2%), fever, and increased liver enzymes. Serious side effects include infections, including life-threatening ones, such as pneumonia, cellulitis, tuberculosis, as well as shingles and other herpes infections.

• Synthese

  
  To a solution of (3S,4R)-3-ethyl-4-(3-tosyl-3H-imidazo[l,2-a]pyrrolo[2,3-e]pyrazin-8-yl)- N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide (10 g) in tetrahydrofurane (50 ml_), a 10% solution of sodium hydroxide in water (15 ml) was added and heated to 50??C. The reaction mixture was stirred for 5 hours and cooled to 25??C. A saturated solution of sodium chloride (100 ml_) was added to the reaction mixture and extracted with dichloromethane (100 ml). The organic phase was separated and washed with water (100 ml_). An 2.5 % aqueous solution of HCI (100 ml) was added and stirred for 30 minutes. The organic phase was removed and the resultant acid aqueous phase was extracted with dichloromethane (100 ml). The final aqueous phase was cooled down to 0/5 ??C and a 10% solution of NaOH was charged until pH 10/12. The resultant suspension was filtered and washed with water (2 x 50 ml_). The cake was drained and dried at 30/40??C under vacuum to give an almost white amorphous solid. Yield: 80%. 1 H NMR (400MHz, d-DMSO) 612.27 (s,1H), 8.58 (s,1H), 7.47-7.43 (m,2H), 7.00-6.94 (m,2H), 4.38 -4.33 (m,1H), 3.92-3.67 (m,5H), 3.33-3.25 (m,1 H), 2.59-2.54 (m,1 H), 1.14-1.08 (m,1 H), 0.86-0.78 (m, 1H), 0.65-0.62 (m, 3H).

• Stoffwechsel

  Upadacitinib displays a dose-proportional pharmacokinetic profile over the therapeutic dose range. Following oral administration, the median time to reach Cmax (Tmax) ranges from 2 to 4 hours. The steady-state plasma concentrations of upadacitinib are reached within 4 days following multiple once-daily administrations, with minimal accumulation. Food intake has no clinically relevant effect on the AUC, Cmax, and Cmin of upadacitinib from the extended-release formulation. Upadacitinib metabolism is mainly mediated by CYP3A4, with a potential minor contribution from CYP2D6. Administration of strong CYP3A inhibitors increases upadacitinib AUC by 75% and Cmax by 70%, while strong inducers of CYP3A reduce upadacitinib plasma exposures by approximately half[1].

• Einzelnachweise

  [1] Mohamed-Eslam F. Mohamed. “Upadacitinib: Mechanism of action, clinical, and translational science.” Cts-Clinical and Translational Science 17 1 (2023).

• Lager

  Store at -20°C

Upadacitinib Upstream-Materialien And Downstream Produkte

Upadacitinib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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