Axitinib Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
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 IC
50s 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.
Chemische Eigenschaften
Off-White Solid
Charakteristisch
Class: receptor tyrosine kinase
Treatment: RCC
Oral bioavailability = 58%
Elimination half-life = 2.5–6.1 h
Protein binding = 99%
Verwenden
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.
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.
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.
Nebenwirkungen
The side effects that you should report to your doctor include:
allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue;
high blood pressure;
seizures;
signs and symptoms of bleeding such as bloody or black, tarry stools; red or dark-brown urine; spitting up blood or brown material that looks like coffee grounds; red spots on the skin; unusual bruising or bleeding from the eye, gums, or nose;
signs and symptoms of a blood clot such as breathing problems; changes in vision; chest pain; severe, sudden headache; pain, swelling, warmth in the leg; trouble speaking; sudden numbness or weakness of the face, arm, or leg;
stomach pain.
The side effects that usually do not require medical attention include constipation cough, diarrhea, loss of appetite, nausea, and vomiting.
Axitinib Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
