319460-85-0 Usage
Description
Axitinib, also known as AG-013736, is a potent VEGFR inhibitor with IC50s of 1.2, 0.25, and 0.29 nM for VEGFR1, -2, and -3, respectively. It also inhibits c-Kit and PDGFRβ with IC50s of 1.7 and 1.6 nM, respectively. Axitinib is a pan VEGF inhibitor that functions by binding to the intracellular tyrosine kinase catalytic domain of VEGF, leading to the blockade of signaling through this angiogenic pathway. It is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ, and c-Kit, and is 50-400 times more potent for VEGF than first-generation inhibitors like sorafenib and sunitinib. Axitinib was discovered by a structure-based drug design approach and binds to the kinase domain of VEGF in a DFG-out conformation. It is an off-white solid and is marketed under the brand name Inlyta.
Used in Oncology:
Axitinib is used as a tyrosine kinase inhibitor for cancer therapy. It is particularly effective in the treatment of advanced renal cell carcinoma (RCC) after the failure of first-line systemic treatment. The US FDA approved axitinib for this indication in January 2012. Axitinib reduces microvessel density, a marker of angiogenesis, and tumor growth in various mouse xenograft models in a dose-dependent manner. It also inhibits VEGF-induced migration and tube formation by human umbilical vein endothelial cells (HUVECs). Formulations containing axitinib have been used in the treatment of renal cell carcinoma.
FDA approved axitinib use of treating advanced kidney cancer
January 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 lookchem of Tian Ye.
Originator
Pfizer (United States)
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.
Synthesis
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’s 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.
Drug interactions
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).
Metabolism
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.
References
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
Check Digit Verification of cas no
The CAS Registry Mumber 319460-85-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 3,1,9,4,6 and 0 respectively; the second part has 2 digits, 8 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 319460-85:
(8*3)+(7*1)+(6*9)+(5*4)+(4*6)+(3*0)+(2*8)+(1*5)=150
150 % 10 = 0
So 319460-85-0 is a valid CAS Registry Number.
InChI:InChI=1/C22H18N4OS/c1-23-22(27)18-7-2-3-8-21(18)28-16-10-11-17-19(25-26-20(17)14-16)12-9-15-6-4-5-13-24-15/h2-14H,1H3,(H,23,27)(H,25,26)/b12-9+
319460-85-0Relevant articles and documents
Axitinib: A Photoswitchable Approved Tyrosine Kinase Inhibitor
Schmidt, Dorian,Rodat, Theo,Heintze, Linda,Weber, Jantje,Horbert, Rebecca,Girreser, Ulrich,Raeker, Tim,Bu?mann, Lara,Kriegs, Malte,Hartke, Bernd,Peifer, Christian
, p. 2415 - 2426 (2018)
The goal of photopharmacology is to develop photoswitchable enzyme modulators as tunable (pro-)drugs that can be spatially and temporally controlled by light. In this context, the tyrosine kinase inhibitor axitinib, which contains a photosensitive stilbene-like moiety that allows for E/Z isomerization, is of interest. Axitinib is an approved drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma. The photoinduced E/Z isomerization of axitinib has been investigated to explore if its inhibitory effect can be turned “on” and “off”, as triggered by light. Under controlled light conditions, (Z)-axitinib is 43 times less active than that of the E isomer in an VEGFR2 assay. Furthermore, it was proven that kinase activity in human umbilical vein cells (HUVECs) was decreased by (E)-axitinib, but only weakly affected by (Z)-axitinib. By irradiating (Z)-axitinib in vitro with UV light (λ=385 nm), it is possible to switch it almost quantitatively into the E isomer and to completely restore the biological activity of (E)-axitinib. However, switching the biological activity off from (E)- to (Z)-axitinib was not possible in aqueous solution due to a competing irreversible [2+2]-photocycloaddition, which yielded a biologically inactive axitinib dimer.
CONTROLLED-RELEASE TYROSINE KINASE INHIBITOR COMPOUNDS WITH LOCALIZED PK PROPERTIES
-
Page/Page column 265-266; 267, (2021/01/22)
The present invention relates to a water-insoluble controlled-release tyrosine kinase inhibitor ( TKI ) compound for use in the treatment of a cell-proliferation disorder, wherein said water-insoluble controlled-release TKI compound releases one or more TKI drug, wherein the water-insoluble controlled-release TKI compound is administered by intra-tissue administration and wherein the total amount of TKI moieties and TKI drug molecules remaining locally in such tissue 3 days after said intra-tissue administration is at least 25% of the amount of TKI moieties or TKI drug molecules administered by said intra-tissue administration; and to related aspects.
Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: Synthesis of axitinib
Yu, Jingbo,Hong, Zikun,Yang, Xinjie,Jiang, Yu,Jiang, Zhijiang,Su, Weike
supporting information, p. 786 - 795 (2018/04/16)
A mechanically-activated chemoselective Heck coupling for the synthesis of 3-vinylindazoles has been developed with the aid of catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical conditions and mechanical parameters, a series of non-activated 3-bromoindazoles and a broad scope of olefins worked well to give the corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib.