Sorafenib

Sorafenib Basic information
Uses Overview Indications Mechanism of action Side effects References
Product Name:Sorafenib
Synonyms:Sorafenib free base for research;Sorafenib Free Base;Forafenib;Sorafenib free base(Bay43-9006);nexavar,sorafenib;BAY43-9006; NEXAVAR;Nexavar;Sorafenib-d4
CAS:284461-73-0
MF:C21H16ClF3N4O3
MW:464.82
EINECS:608-209-4
Product Categories:Bay 43-9006;All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Pharmaceutical intermediate;Sorafinib;Molecular Targeted Antineoplastic;anti-neoplastic;Amines;Inhibitor;284461-73-0
Mol File:284461-73-0.mol
Sorafenib Structure
Sorafenib Chemical Properties
Melting point 202-204°C
Boiling point 523.3±50.0 °C(Predicted)
density 1.454±0.06 g/cm3(Predicted)
vapor pressure 0Pa at 25℃
storage temp. Sealed in dry,Store in freezer, under -20°C
solubility Chloroform (Slightly), DMSO (Slightly)
pka12.89±0.70(Predicted)
form White to off-white solid.
color White to Off-White
Water Solubility 100μg/L at 20℃
LogP3.3 at 25℃
CAS DataBase Reference284461-73-0(CAS DataBase Reference)
Safety Information
Risk Statements 68/20/21/22-37/38
Safety Statements 36-37-39
HS Code 29350090
Hazardous Substances Data284461-73-0(Hazardous Substances Data)
MSDS Information
Sorafenib Usage And Synthesis
UsesSorafenib, an orally active potent multi-kinases inhibitor,was approved in the U.S. for the treatment of advanced renalcell carcinoma. The drug targets both tumor cell proliferationand tumor angiogenesis kinases that include RAF,VEGFR-2, VEGFR-3, PDGFR-b, KIT and FLT-3. Sorafenibis being jointly developed by Bayer and Onyx in phase IIItrials as a single agent for the treatment of advanced hepato-cellular carcinoma and in combination with carboplatin andpaclitaxel in patients with advanced metastatic melanoma.Phase II trials in combination with doxorubicin for thetreatment of advanced hepatocellular carcinoma are alsounder investigation. Additional phase II trials are ongoingfor non-small cell lung cancer (NSCLC) and in postmenopausalwomen with estrogen receptor and/or progesteronereceptor-positive metastatic breast cancer. In addition, theNational Cancer Institute (NCI) is evaluating the compoundboth as a single therapy agent and in combination with otheroncology agents in phase II trials for several cancer indications.
OverviewSorafenib tosylate is the tosylate form of sorafenib, which is a drug approved for the treatment of hepatocellular carcinoma and the treatment of advanced renal cell carcinoma (primary kidney cancer).  Sorafenib is an oral receptor tyrosine kinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases (vascular endothelial growth factor receptors 1, 2, 3 and platelet-derived growth factor-b, Flt-3 and c-kit) that are implicated in tumorigenesis and tumor progression.
IndicationsIt is indicated for the treatment of hepatocellular carcinoma and the treatment of advanced renal cell carcinoma (primary kidney cancer).
Mechanism of actionThe bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits both cell surface tyrosine kinase receptors and downstream intracellular serine/threonine kinases in the Ras/MAPK cascade.[2-4] Receptor tyrosine kinases inhibited by sorafenib include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-b, c-KIT, FMS-like tyrosine kinase 3 (FLT-3) and RET. Intracellular Raf serine/threonine kinase isoforms inhibited by sorafenib include Raf-1 (or C-Raf), wild-type B-Raf and mutant B-Raf.[3, 4] These kinases are involved in tumour cell proliferation and tumour angiogenesis.[3, 4]
The antiproliferative activity of sorafenib is variable in different tumor types and largely depends on the oncogenic signaling pathways that mediate tumor proliferation. Sorafenib has also been shown to induce apoptosis in several tumor cell lines. Although the mechanism through which sorafenib induces apoptosis is not fully elucidated and may vary between cell lines, a commonly observed theme is the inhibition of phosphorylation of the initiation factor eIF4E and loss of the antiapoptotic protein myeloid cell leukemia-1 (MCL-1)[5]. Recently, sorafenib was shown to inhibit hepatitis C viral replication in vitro[6], and in vitro studies have also shown some direct effects on immune cells [7]. Whether these effects
Side effectsThe most common adverse reactions (20%), considered to be related to sorafenib, in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain [12].
Less frequent side effects (> 1 -10) include cardiac ischemia/infarction (3%), flushing, headache (10%), depression, fever, acne, exfoliative dermatitis, decreased appetite, dyspepsia, dysphagia, esophageal varices bleeding (2%), glossodynia, mucositis, stomatitis, xerostomia, erectile dysfunction, anemia, transaminases increased (transient), joint pain (10%), arthralgia, myalgia, hoarseness and flu-like syndrome.
Rare (< 1%) side effects of sorafenib include acute renal failure, alkaline phosphatase increased, arrhythmia, bilirubin increased, bone pain, cardiac failure, cerebral hemorrhage, congestive heart failure, dehydration, eczema, epistaxis, erythema multiforme, folliculitis, gastritis, gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal reflux, gynecomastia, hypersensitivity (skin reaction, urticaria), hypertensive crisis, hyponatremia, hypothyroidism, infection, jaundice, myocardial infarction (MI), mouth pain, myocardial ischemia, pancreatitis, pleural effusion, preeclampsialike syndrome (reversible hypertension and proteinuria), renal failure, respiratory hemorrhage, reversible posterior leukoencephalopathy syndrome (RPLS), rhinorrhea, skin cancer (squamous cell/keratoacanthomas), thromboembolism, tinnitus, transient ischemic attack, tumor lysis syndrome, tumor pain and voice alteration.
References
  1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007 Jun; 132 (7): 2557-76
  2. Adnane L, Trail PA, Taylor I, et al. Sorafenib (BAY 439006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol 2005; 407: 597-612
  3. Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006 Oct; 5 (10): 835-44
  4. Wilhelm SM, Carter C, Tang LY, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004 Oct 1; 64 (19): 7099-109
  5. Yu C, Bruzek LM, Meng XW, et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 2005;24:6861-9
  6. Himmelsbach K, Sauter D, Baumert TF, et al. New aspects of an anti-tumour drug: sorafenib efficiently inhibits HCV replication. Gut 2009;58:1644-53
  7. Molhoek KR, McSkimming CC, Olson WC, et al. Apoptosis of CD4(+) CD25(high) T cells in response to Sirolimus requires activation of T cell receptor and is modulated by IL-2. Cancer Immunol Immunother 2009;58:867-76
  8. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol 2005;23:965-72
  9. Clinical Pharmacology and Biopharmaceutics NDA Review for Sorafenib Tosylate (NDA 21 923), F.C.F.D.E.A. RESEARCH, Editor, 2005
  10. BAY 43-9006 (sorafenib) Investigator’s Brochure. Bayer Healthcare AG,Version 10.0, July 1, 2009
  11. European Medicines Agency. Sorafenib (Nexavar): summary of product characteristics [online].
  12. Blanchet B, Billemont B, Barete S, et al. Toxicity of sorafenib: clinical and molecular aspects. Expert Opin Drug Saf 2010;9:275-87
  13. https://www.drugs.com/cdi/sorafenib.html
DescriptionSorafenib 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.
Chemical PropertiesLight Yellow Solid
OriginatorBayer/Onyx (Germany)
UsesA potent RAF kinase inhibitor. Antineoplastic
UsesMultiple kinase inhibitor targeting both RAF kinase and receptor tyrosine kinases that promote angiogensis. Antineoplastic.
UsesSorafenib 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.
IndicationsSorafenib (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.
Brand nameNexavar (Bayer HealthCare); Xarelto (Bayer HealthCare).
Flammability and ExplosibilityNonflammable
Clinical UseProtein kinase inhibitor:
Treatment of advanced renal cell carcinoma
Treatment of hepatocellular carcinoma
Treatment of thyroid cancer


SynthesisAn 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.

Synthesis_284461-73-0


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


MetabolismSorafenib 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.
storageStore at -20°C
SORAFENIB N-OXIDE Chlorantraniliprole Methylparaben Formamide,Deionized Methyl Acetonitrile Vatalanib base N,N-Dimethylformamide Diphenyldiethoxysilane Basic Violet 1 Pirfenidone Difluorochloromethane Trifluoromethyl PHENYL VALERATE Benzamide Methanol Methyl acrylate Formamide

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