Tofacitinib

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H410：Sehr giftig für Wasserorganismen mit langfristiger Wirkung.

• Sicherheit

  P273：Freisetzung in die Umwelt vermeiden.

  P391：Verschüttete Mengen aufnehmen.

Tofacitinib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  In November 2012, the US FDA approved tofacitinib (also referred to as CP-690550) for the treatment of adult patients with moderate to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate. Tofacitinib is the first small molecule kinase inhibitor approved for the treatment of RA. Tofacitinib is an inhibitor of the four subtypes of Janus kinase (JAK): JAK1, JAK2, JAK3, and Tyk2. The JAKs are intracellular, nonreceptor tyrosine kinases that play important roles in the signal transduction pathway of many cytokines (e.g., interleukins 2, 4, 7, 9, 15, and 21) and are involved in the propagation of inflammation in RA. Tofacitinib acts by inhibiting the phosphorylation and activation of signal transducers and activators of transcription (STATs), thereby suppressing the production of inflammatory mediators in joint tissue. At the enzyme level, tofacitinib inhibits JAKs 1, 2, 3, and Tyk2 with IC_50s of 3.2, 4.1, 1.6, and 34 nM, respectively. At the cellular level, tofacitinib inhibits the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC_50s of 406, 56, and 1377 nM, respectively.

• Chemische Eigenschaften

  Light Pink to Pale Orange Solid

• Originator

  Pfizer (United States)

• Charakteristisch

  Class: non-receptor tyrosine kinase
  Treatment: RA, PA, JIA, UC
  Oral bioavailability = 74%
  Elimination half-life = 3.2 h
  Protein binding = 40%

• Verwenden

  CP-690550 is a pyrrolo[2,3-d]pyrimidine derivative, as Janus kinase inhibitor for treatment of rheumatoid arthritis

• Indications

  The JAK family includes four isoforms, JAK1, JAK2, JAK3, and tyrosine kinase (TYK2). Ruxolitinib (Jakafi(R), Incyte Corp.) was the first approved JAK inhibitor, which inhibits both JAK1 and JAK2, used for the treatment of different types of myelofibrosis. Tofacitinib (Xeljanz(R), Pfizer) was approved by FDA as a JAK3-selective inhibitor for the treatment of rheumatoid arthritis and is one of the only two FDA-approved kinase inhibitors for non-oncological indications.

• Definition

  ChEBI: A pyrrolopyrimidine that is pyrrolo[2,3-d]pyrimidine substituted at position 4 by an N-methyl,N-(1-cyanoacetyl-4-methylpiperidin-3-yl)amino moiety. Used as its citrate salt to treat moderately to severely ctive rheumatoid arthritis.

• Trademarks

  Xeljanz

• Pharmakokinetik

  Tofacitinib has good solubility (>4 mg/mL in water for the crystalline citrate salt), which contributes to its excellent oral bioavailability (74%) in healthy volunteers. However, tofacitinib exhibits relatively short elimination half-life of 3.2 hours, and its protein binding is very low (approximately 40%, predominantly to albumin). Tofacitinib undergoes major hepatic clearance (70% of total clearance) and minor renal clearance (30%). The metabolism of tofacitinib proceeds primarily in the liver by CYP3A4 (major) and CYP2C19 (minor), resulting in oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation, and glucuronidation. As opposed to the longer half-life of biologics, small-molecule JAK inhibitors such as tofacitinib typically display much shorter half-lives with once or twice-daily dosing regimens, which may be inconvenient to some patients. However, the shorter half-life ensures faster recovery to the full ability to fight infections which may occur with any immune suppressing medication.

• Clinical Use

  Tofacitinib was approved for treating rheumatoid arthritis in 2012, joint pain and swelling, psoriatic arthritis in 2017, and ulcerative colitis in 2018. However, severe side effects observed during clinical studies prevented the FDA from approving more efficacious doses for the treatment of rheumatoid arthritis (RA). Tofacitinib also carries a black box warning for an increased risk of pulmonary embolism and death associated with the 10 mg BID dose.

• Synthese

  Commercially available aminopyridine 171 was reacted with dimethyl dicarbonate in the presence of potassium t-butoxide to give the methyl carbamate 172 in 87% yield. Hydrogenation of this carbamate 172 in the presence of 20 wt% of 5% Rh/C (JM type C101023-5) in acetic acid followed by reductive amination with benzaldehyde and sodium triacetoxy borohydride furnished the cis-benzyl protected piperidine 173 in 73% yield. Reduction of the methyl carbamate within 173 with lithium aluminum hydride (LAH) in THF gave the corresponding methyl amino piperidine which was isolated as the dihydrochloride salt 174 in 87% yield. Enantiomeric resolution of the methyl amino piperidine was achieved by freebasing the di-hydrochloride salt 174 with sodium hydroxide and then conversion to the di-toluol-L-tartaric acid salt followed by crystallization to give 175 in 42% yield and 98.6% ee. The enantioenriched tartrate salt 175 was then directly reacted with dichloride 176 (obtained from reaction of commercial 7H-pyrrolo[2,3-d]pyrimidine-2,4-diol (178) with phosphorous oxychloride) in the presence of potassium carbonate in water to give the coupled product 177 in essentially quantitative yield. Hydrogenation of intermediate 177 with DeGussa?ˉs catalyst triggered concomitant debenzylation and chloride removal, and this was followed by installation of the cyanoacetate group and subsequent treatment with citric acid to provide tofacitinib citrate (XXVII) in 90% yield.

  

• Einzelnachweise

  1) Jiang et al. (2008), Examining the chirality, confirmation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitril (CP-690,550); J. Mol. Chem., 51 8012 2) Cutolo and Meroni (2013), Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis; J. Inflamm. Res., 6 129 3) Martina et al. (2016), Inhibition of JAK3 and PKC via Immunosuppressive Drugs Tofacitinib and Sotrastaurin Inhibits Proliferation of Human B Lymphocytes In Vitro; Transplant. Proc., 48 3046 4) Moisan et al. (2015), White-to-brown metabolic conversion of human adipocytes by JAK inhibition; Nat. Cell Biol., 17 57 5) Dowty et al. (2014), Preclinical to clinical translation of tofacitinib, a Janus kinase inhibitor, in rheumatoid arthritis; J. Pharmacol. Exp. Ther., 348 165

Tofacitinib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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