Axitinib

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H302：Gesundheitsschädlich bei Verschlucken.

  H400：Sehr giftig für Wasserorganismen.

• Sicherheit

  P273：Freisetzung in die Umwelt vermeiden.

Axitinib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  In January 2012, the US FDA approved axitinib (also referred to as AG-013736) for the treatment of advanced renal cell carcinoma (RCC) for patients who have not responded to prior therapy. Axitinib is a pan VEGF inhibitor and functions by binding to the intracellular tyrosine kinase catalytic domain of VEGF leading to blockade of signaling through this angiogenic pathway. Axitinib is50–400 times more potent for VEGF (enzyme Ki and cellular IC_50s for VEGF 1, 2, and 3 are ～0.1 nM) than first-generation inhibitors like sorafenib and sunitinib. Axitinib also inhibits c-Kit and PDGFR(α/β) with enzyme Ki's of ～2 nM and was selective when tested against a broad panel of other protein kinases. Axitinib was discovered by a structure-based drug design approach and binds to the kinase domain of VEGF in a DFG-out conformation. Axitinib blocks VEGF-2 phosphorylation up to 7 h postdose in vivo and inhibits endothelial cell proliferation in xenograft tumors implanted in mice. Synthetic routes to axitinib employing a Migita coupling to form the diaryl sulfide and a Heck reaction to install the 2-styrylpyridine moiety have been reported.

• Beschreibung

  Axitinib is a VEGFR inhibitor (IC₅₀s = 1.2, 0.25, and 0.29 nM for VEGFR1, -2, and -3, respectively). It also inhibits c-Kit and PDGFRβ (IC₅₀s = 1.7 and 1.6 nM, respectively). It inhibits VEGF-induced migration of and tube formation by human umbilical vein endothelial cells (HUVECs). Axitinib (1-100 mg/kg) reduces microvessel density, a marker of angiogenesis, and tumor growth in MV522 colon carcinoma, A375 melanoma, SN12C-GFP renal carcinoma, and U87 glioma mouse xenograft models in a dose-dependent manner. Formulations containing axitinib have been used in the treatment of renal cell carcinoma.

• Chemische Eigenschaften

  Off-White Solid

• Originator

  Pfizer (United States)

• Charakteristisch

  Class: receptor tyrosine kinase
  Treatment: RCC
  Oral bioavailability = 58%
  Elimination half-life = 2.5–6.1 h
  Protein binding = 99%

• Verwenden

  Axitinib is a tyrosine kinase inhibitor. Axitinib is used in cancer therapy.

• Verwenden

  Axitinib (AG-013736) is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM, respectively.

• Definition

  ChEBI: An indazole substituted at position 3 by a 2-(pyridin-2-yl)vinyl group and at position 6 by a 2-(N-methylaminocarboxy)phenylsulfanyl group. Used for the treatment of advanced renal cell carcinoma after failure of a first line systemic tr atment.

• Trademarks

  Inlyta

• Biochem/physiol Actions

  Axitinib (AG-013736) is an orally available, potent (picomolar) and selective tyrosine kinase inhibitor that blocks VEGF receptors 1, 2 and 3. The drug blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase.

• Clinical Use

  Sold under the brand name Inlyta® by Pfizer, Inc., axitinib was approved by the FDA in January 2012 for the treatment of advanced renal cell carcinoma (RCC), specifically after the failure of other systemic treatments. Axitinib slows cancer cell proliferation by inhibition of the vascular endothelial growth factor (VEGF)/VEGF receptor tyrosine (RTK) signaling pathway. In particular, axitinib is a potent inhibitor of VEGF/RTK 1-3, which selectively slows angiogenesis, vascular permeability, and blood flow in solid tumors.

• Nebenwirkungen

  The side effects that you should report to your doctor include:
  allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue;
  high blood pressure;
  seizures;
  signs and symptoms of bleeding such as bloody or black, tarry stools; red or dark-brown urine; spitting up blood or brown material that looks like coffee grounds; red spots on the skin; unusual bruising or bleeding from the eye, gums, or nose;
  signs and symptoms of a blood clot such as breathing problems; changes in vision; chest pain; severe, sudden headache; pain, swelling, warmth in the leg; trouble speaking; sudden numbness or weakness of the face, arm, or leg;
  stomach pain.
  The side effects that usually do not require medical attention include constipation cough, diarrhea, loss of appetite, nausea, and vomiting.
  

• Synthese

  Numerous patents and papers have been disclosed on the synthesis of axitinib, a recently published manuscript details the development of the manufacturing route, and this route is depicted in the scheme. The synthesis began with Migita coupling of commercial iodide 17 with thiophenol 18. Interestingly, this transformation?ˉs efficiency relied upon attention to the number of equivalents of base and an inert atmosphere in the reaction vessel, conditions which minimized catalyst poisoning during the reaction. Without isolation, indazole 19 was iodinated to afford diarylthioether 20 in 85-90% yield over the two steps. Protection of the indazole within 20 as its acetamide preceeded a Heck reaction with 2-vinylpyridine, and then subsequent removal of the indazole protection followed by a series of recrystallizations yielded axitinib (IV) in a combined 62% yield over the final 4 steps.

  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Antipsychotics: avoid with clozapine (increased risk of agranulocytosis); avoid with pimozide.
  Concomitant use with strong CYP3A4/5 inhibitors: avoid; however, if concomitant use cannot be avoided then reduce the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability; if CYP3A4/5 inhibitor is discontinued, then increase the axitinib dose used prior to initiation of the strong inhibitor after 3-5 half-lives of the inhibitor (strong CYP3A4/5 inhibitors include ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, ritonavir, saquinavir, and voriconazole).

• Stoffwechsel

  Axitinib is metabolised primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Most of the drug is excreted via the faeces and urine as metabolites.

• Lager

  Store at +4°C

• Einzelnachweise

  1) Hu-Lowe?et al.?(2008),?Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1,2,3; Cancer Res.,?14?7272 2) Ma and Waxman (2008),?Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib; Mol. Cancer Ther.,?7?79 3) Pemovska?et al.?(2015),?Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation; Nature,?519?102 4) Rixe?et al.?(2007),?Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer; a phase II study; Lancet Oncol.,?8?975 5) Yuan?et al.?(2014),?Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation;?Biomed.Pharmacother.?68?751 6) Zhang?et al.?(2014),?Axitinib, a selective inhibitor of vascular endothelial growth factor receptor, exerts an anticancer effect in melanoma through promoting antitumor immunity;?Anticancer Drugs?25?204

Axitinib Upstream-Materialien And Downstream Produkte

Axitinib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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