Axitinib

Axitinib Basic information
FDA approved axitinib use of treating advanced kidney cancer
Product Name:Axitinib
Synonyms:N-METHYL-2-{[3-((E)-2-PYRIDIN-2-YLVINYL)-1H-INDAZOL-6-YL]SULFANYL}BENZAMIDE;N-Methyl-2-((3-((1E)-2-(pyridin-2-yl)ethenyl)-1H-indazol-6-yl)sulfanyl)benzamide;AVERMECTINB;Axitinib for research;AG 013736;N-Methyl-2-[[3-[(1E)-2-(2-pyridinyl)ethenyl]-1H-indazol-6-yl]thio]benzamide;Benzamide, N-methyl-2-[[3-[(1E)-2-(2-pyridinyl)ethenyl]-1H-indazol-6-yl]thio]-;AG013736; AG 013736; AG-013736; AXITINIB; BRAND NAME: INLYTA.
CAS:319460-85-0
MF:C22H18N4OS
MW:386.47
EINECS:638-771-6
Product Categories:Pfizer compounds;API;All Inhibitors;Inhibitors;AG 013736;chemical;Intermediates & Fine Chemicals;Pharmaceuticals;Protein Kinase Inhibitors and Activators;319460-85-0
Mol File:319460-85-0.mol
Axitinib Structure
Axitinib Chemical Properties
Melting point 213-215°C
Boiling point 668.9±55.0 °C(Predicted)
density 1.4
storage temp. room temp
solubility DMSO: ≥8mg/mL
pka12.70±0.40(Predicted)
form powder
color white to tan
Stability:Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
InChIKeyRITAVMQDGBJQJZ-FMIVXFBMSA-N
CAS DataBase Reference319460-85-0(CAS DataBase Reference)
Safety Information
Hazard Codes Xn,N
Risk Statements 22-50/53
Safety Statements 60-61
RIDADR UN 3077 9 / PGIII
WGK Germany 3
HS Code 29333990
MSDS Information
Axitinib Usage And Synthesis
FDA approved axitinib use of treating advanced kidney cancerJanuary 27, 2012, the FDA approved axitinib for the treatment of advanced kidney cancer (renal cell carcinoma) which other drugs unanswer . Inlyta is manufactured and sold by Pfizer,and is a oral pill taken twice a day.
Renal cell carcinoma is a type of tumor originating from the tubular endothelial cells. Axitinib can prevent certain protein called kinases playing a role in tumor growth and metastasis .
Axitinib is a small molecule tyrosine kinase inhibitor, effective against multiple targets, including VEGF receptors 1, 2 and 3.
Dr. Richard Pazdur, hematology and oncology drugs office director of FDA Drug Evaluation and Research Centre, said: "This is the seven kind of drugs allowed treating metastatic or advanced renal cell carcinoma since 2005 . Overall, during this time ,record level of drug development has dramatically changed the treatment of metastatic renal cell carcinoma paradigm, and offers a variety of treatment options for patients. "
In recent years, the drug has been approved for the treatment of kidney cancer include sorafenib (2005), sunitinib (2006), temsirolimus(2007), everolimus (2009), bevacizumab(2009) and pazopanib(2009).
The above information is edited by the chemicalbook of Tian Ye.




DescriptionAxitinib 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.
DescriptionIn 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 IC50s 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.
Chemical PropertiesOff-White Solid
OriginatorPfizer (United States)
UsesA tyrosine kinase inhibitor; used in cancer therapy.
UsesAxitinib (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.
UsesAxitinib 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.
UsesAxitinib is a tyrosine kinase inhibitor. Axitinib is used in cancer therapy.
DefinitionChEBI: 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.
Brand nameInlyta
Biochem/physiol ActionsAxitinib (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 UseSold 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.
SynthesisNumerous 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.

Synthesis_319460-85-0

Drug interactionsPotentially 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).

MetabolismAxitinib 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.
storageStore at +4°C
References1) 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 Preparation Products And Raw materials
Raw materialsBenzaMide, 2-[(3-iodo-1H-indazol-6-yl)thio]-N-Methyl--->2-Vinylpyridine
BKM-120 Tofacitinib Afatinib Crizotinib Lenvatinib Sunitinib Malate Dacomitinib (PF299804) CO-1686 Neratinib Trametinib lenvatinib Mesylate Dasatinib Palbociclib Bosutinib Cabozantinib GZD 824 Nilotinib hydrochloride anhydrous Axitinib

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