319460-85-0 Usage
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.
Description
Different sources of media describe the Description of 319460-85-0 differently. You can refer to the following data:
1. 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.
2. 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 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 Properties
Off-White Solid
Originator
Pfizer (United States)
Uses
Different sources of media describe the Uses of 319460-85-0 differently. You can refer to the following data:
1. A tyrosine kinase inhibitor; used in cancer therapy.
2. 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.
3. Axitinib 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.
4. Axitinib is a tyrosine kinase inhibitor. Axitinib is used in cancer therapy.
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.
Brand name
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.
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.
Photoswitchable azo‐ and diazocine‐functionalized derivatives of the vegfr‐2 inhibitor axitinib
Heintze, Linda,Schmidt, Dorian,Rodat, Theo,Witt, Lydia,Ewert, Julia,Kriegs, Malte,Herges, Rainer,Peifer, Christian
, p. 1 - 23 (2020/11/30)
In this study, we aimed at the application of the concept of photopharmacology to the approved vascular endothelial growth factor receptor (VEGFR)‐2 kinase inhibitor axitinib. In a previous study, we found out that the photoisomerization of axitinib’s stilbene‐like double bond is unidirectional in aqueous solution due to a competing irreversible [2+2]‐cycloaddition. Therefore, we next set out to azologize axitinib by means of incorporating azobenzenes as well as diazocine moieties as photoresponsive elements. Conceptually, diazocines (bridged azobenzenes) show favorable photoswitching properties compared to standard azobenzenes because the thermodynamically stable Z‐isomer usually is bioinactive, and back isomerization from the bioactive E‐isomer occurs thermally. Here, we report on the development of different sulfur– diazocines and carbon–diazocines attached to the axitinib pharmacophore that allow switching the VEGFR‐2 activity reversibly. For the best sulfur–diazocine, we could verify in a VEGFR‐2 kinase assay that the Z‐isomer is biologically inactive (IC50 >> 10,000 nM), while significant VEGFR‐2 inhibition can be observed after irradiation with blue light (405 nm), resulting in an IC50 value of 214 nM. In summary, we could successfully develop reversibly photoswitchable kinase inhibitors that exhibit more than 40‐fold differences in biological activities upon irradiation. Moreover, we demonstrate the potential advantage of diazocine photoswitches over standard azobenzenes.
Method for preparing axitinib and intermediates thereof
-
, (2018/05/30)
The invention discloses a method for preparing axitinib and intermediates thereof. A chemical name of the axitinib is N-methyl-2-[(3-(1E-2-(pyridine-2-yl)ethylene)-1H-indazole-6-yl)sulfur]benzamide, and a chemical formula of the axitinib is C22H18N4OS. The preparation process disclosed by the invention is simple in process, readily available in raw materials, economic, environmentally friendly, high in product yield and product purity, contributes to realizing industrialization, reduces the production cost and is suitable for mass production. The provided novel intermediates and the preparation method thereof have significance on the economic technology of the axitinib.
