Sorafenib

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.

Sorafenib Chemische Eigenschaften,Einsatz,Produktion Methoden

• Beschreibung

  Sorafenib is a small molecular inhibitor of several kinases involved in tumor angiogenesis and proliferation, including, but not limited to, Raf (IC₅₀=12nM for Raf-1), VEGFR (IC₅₀=90nM for VEGFR-2 and IC₅₀=12nM for VEGFR-3), and platelet derived growth factor receptor (IC₅₀=57nM for PDGFR-b). Specifically, sorafenib blocks tumor progression by inhibiting cellular proliferation that is dependent on activation of the MAPK pathway (Raf) and/or inhibiting tumor angiogenesis through VEGFR and/or PDGFR. While it may be effective in the treatment of a variety of tumors, the first approvable indication is for renal cell carcinoma. Overall, the drug appears to be well tolerated by the majority of patients at the 400 mg b.i.d. continuous dosing. As an inhibitor of multiple kinases vital for tumor progression, sorafenib may possess wide-spectrum antitumor properties and may emerge as an effective weapon against a variety of solid tumors.

• Chemische Eigenschaften

  Light Yellow Solid

• Originator

  Bayer/Onyx (Germany)

• Charakteristisch

  Class: receptor tyrosine kinase
  Treatment: RCC, HCC, thyroid cancer
  Elimination half-life = 25–48 h
  Protein binding = 99.7%

• Charakteristisch

  The complex of sorafenib with a nonphosphorylated VEGFR2 construct comprising the catalytic and juxtamembrane (JM) domain shows the activation loop adopts a DFG-out position. The net effect of sorafenib’s interactions with the kinase is to stabilize the DFG motif in an inactive conformation. The lipophilic trifluoromethyl phenyl ring at the opposite end of the molecule inserts into a hydrophobic pocket formed between the -C and -E helices and amino-terminal regions of the DFG motif and catalytic loop. The urea functionality forms two crucial hydrogen bonds, one with the backbone aspartate of the DFG loop and the other with the glutamate side chain of the -C helix. In the auto-inhibited state, the DFG-out segment, particularly Phe1047, blocks ATP-binding. When the JM rearranges out of the regulatory domain pocket (RDP), then the DFG is unlocked and able to switch to the open activated state. Autophosphorylation, which activates the kinase presumably through stabilization of an active conformation, was shown to occur on the JM and then the DFG-containing activation loop sequentially. Sorafenib fills the binding channel, making an important H-bond to Asp1046, two H-bonds to the side chain carboxylate oxygen of Glu885, and two H-bonds to Cys919. The selectivity of sorafenib derives from the formation of these four hydrogen bonds and attractive van der Waals (dispersion) interactions.

• Verwenden

  Sorafenib Tosylate (Bay 43-9006, Nexavar) is a small molecular inhibitor of VEGFR, PDGFR, c-Raf and B-Raf with IC50s of 18 nM, 10 nM, 3 nM and 15 nM, respectively.

• Verwenden

  Multiple kinase inhibitor targeting both RAF kinase and receptor tyrosine kinases that promote angiogensis. Antineoplastic.

• Verwenden

  A potent RAF kinase inhibitor. Antineoplastic

• Indications

  Sorafenib (Nexavar(R), Bayer) was the first approved inhibitor targeting the vascular endothelial growth factor (VEGF) family kinases, which include VEGFR1, VEGR2, and VEGFR3. Sorafenib was originally approved for the treatment of renal cell carcinoma (RCC) in 2005, hepatocellular carcinoma in 2007, and locally recurrent or metastatic thyroid carcinoma refractory to radioactive iodine treatment in 2013. Six other approved inhibitors with VEGFRs as the main targets are sunitinib (Sutent(R), Pfizer) for RCC, soft tissue sarcoma, thyroid cancer,metastatic pancreatic tumors, gastrointestinal stromal tumor, and several other types of carcinomas; pazopanib (Votrient(R), GlaxoSmithKline) for RCC, soft tissue sarcoma, and thyroid cancer; axitinib (Inlyta(R), Pfizer) for RCC,thyroid cancer, and aplastic anemia, as well as T315I-mutant Bcr–Abl1-driven leukemia; regorafenib (Stivarga(R), Bayer) for gastrointestinal stromal tumors and colorectal cancer; nintedanib (Ofev(R), Boehringer Ingelheim) for the non-oncological indication of idiopathic pulmonary fibrosis; and lenvatinib (Lenvima(R), Eisai Inc.) for RCC and different types of thyroid cancers. Sunitinib, pazopanib, and lenvatinib bind to the “DFG-in”conformation of VEGFRs, while axitinib, regorafenib, and nintedanib bind to inactive VEGFRs adopting the “DFG-out”conformation.

• Definition

   ChEBI: Sorafenib is a member of the class of phenylureas that is urea in which one of the nitrogens is substituted by a 4-chloro-3-trifluorophenyl group while the other is substituted by a phenyl group which, in turn, is substituted at the para position by a [2-(methylcarbamoyl)pyridin-4-yl]oxy group. It has a role as an antineoplastic agent, an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor, a tyrosine kinase inhibitor, an angiogenesis inhibitor, an anticoronaviral agent and a ferroptosis inducer. It is a pyridinecarboxamide, a member of monochlorobenzenes, an aromatic ether, a member of (trifluoromethyl)benzenes and a member of phenylureas.

• Trademarks

  Nexavar (Bayer HealthCare); Xarelto (Bayer HealthCare).

• Flammability and Explosibility

  Non flammable

• Clinical Use

  Protein kinase inhibitor:
  Treatment of advanced renal cell carcinoma
  Treatment of hepatocellular carcinoma
  Treatment of thyroid cancer

• Synthese

  An improved, four-step synthesis in 63% overall yield was published recently and is illustrated in the scheme. Picolinic acid (127) was heated with Vilsmeier reagent for 16 hr to give 128 in 89% yield as an off-white solid. The acid chloride 128 was treated with methylamine in methanol at low temperature to give amide 129 in 88% yield as paleyellow crystals after its crystallization from ethyl acetate.
  4-Aminophenol anion was generated under a basic condition and compound 129 was added to the anion solution to give corresponding addition compound 131 in 87% yield. For an unknown reason, potassium carbonate used in the reaction increased the reaction rate significantly. Finally, compound 131 was condensed with isocyanate 132 in methylene chloride to give sorafenib (XVIII) in 92% yield as a white solid.

  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Anticoagulants: may enhance effect of coumarins.
  Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
  Antivirals: avoid with boceprevir.

• Stoffwechsel

  Sorafenib is metabolised primarily in the liver and undergoes oxidative metabolism mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. 8 metabolites have been identified, during in vitro studies one has been shown to have equal activity to sorafenib. About 96% of a dose is excreted within 14 days, with 77%, mostly as unchanged drug, recovered in the faeces, and 19% in the urine as glucuronidated metabolites.

• Lager

  Store at -20°C

Sorafenib Upstream-Materialien And Downstream Produkte

Sorafenib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

Global(596)Suppliers

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