Regorafenib

Bezeichnung:Regorafenib

CAS-Nr755037-03-7

Englisch Name:Regorafenib

CBNumberCB32498792

SummenformelC21H15ClF4N4O3

Molgewicht482.82

MOL-Datei755037-03-7.mol

Regorafenib physikalisch-chemischer Eigenschaften

Schmelzpunkt	206.0 to 210.0 °C
Siedepunkt	513.4±50.0 °C(Predicted)
Dichte	1.491±0.06 g/cm3(Predicted)
storage temp.	Refrigerator
Löslichkeit	DMSO (Slightly), Methanol (Slightly)
pka	12.04±0.70(Predicted)
Aggregatzustand	White powder.
Farbe	Pale Pink to Light Pink
CAS Datenbank	755037-03-7

Sicherheit

HS Code

29242990

Gefahreninformationscode (GHS)

Regorafenib Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
In September 2012, theUSFDAapproved regorafenib for the treatment of patients with metastatic colorectal cancer (CRC), especially those for whom standard therapies have failed, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, ananti-EGFRtherapy. Regorafenib is a multikinase inhibitor with potent inhibitory activity versus VEGFRs and PDFRs. Both of these classes of receptors are expressed on tumor cells and affect proliferation and angiogenesis. Regorafenib inhibited growth in murine xenograft models for colon, breast, renal, lung, melanoma, pancreatic, and ovarian tumors when dosed at 10–30 mg/kg. Regorafenib is a fluorinated analog of sorafenib, a multikinase inhibitor co-marketed by Bayer and Onyx for the treatment of kidney and liver cancer. The synthesis of regorafenib is accomplished in two steps from commercially available starting materials. 4-Aminophenol is coupled to 4-chloro-N-methyl- 2-pyridinecarboxamide to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. Subsequent treatment with 4-chloro-3-(trifluoromethyl)phenyl isocycanate affords the urea, regorafenib.
Beschreibung
Regorafenib is an orally bioavailable multi-kinase inhibitor with anticancer activity. It inhibits RET, C-RAF, VEGFR2, c-Kit, VEGFR1, and PDGFRβ with IC₅₀ values of 1.5, 2.5, 4.2, 7, 13, and 22 nM, respectively. Regorafenib also inhibits B-RAF, VEGFR3, FGFR, and Tie2 (IC₅₀s = 28, 46, 202, and 311 nM, respectivey) as well as other kinases. In vivo, regorafenib (10 mg/kg) reduces tumor size in the MDA-MB-231 breast and 786-O renal cancer mouse xenograft models. It also reduces tumor microvessel area and inhibits tumor growth in a panel of mouse xenograft models. Formulations containing regorafenib have been used in the treatment of advanced gastrointestinal stromal tumors and metastatic colorectal cancer.
Originator
Bayer (Germany)
Charakteristisch
Class: receptor tyrosine kinase
Treatment: colorectal cancer, GIST, HCC
Elimination half-life = 26-28 h
Protein binding = 99.5%
Verwenden
It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent.
Verwenden
BAY 73-4506 (Regorafenib) is a multikinase inhibitor with IC50 of 17, 40 and 69 nM c-KIT, VEGFR2, B-Raf.
Verwenden
Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively
Definition
ChEBI: A pyridinecarboxamide obtained by condensation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]pyridine-2-carboxylic acid with methylamine. Used for for the treatment of metastatic colorectal cancer in patients who have previ usly received chemotherapy, anti-EGFR or anti-VEGF therapy.
Trademarks
Stivarga
Clinical Use

Treatment of colorectal cancer and gastrointestinal stromal tumours
Treatment of hepatocellular carcinoma
target
VEGFR1/2/3
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Analgesics: avoid with mefenamic acid.
Antibacterials: concentration reduced by rifampicin - avoid.
Anticoagulants: increased risk of bleeding with warfarin.
Antifungals: concentration increased by ketoconazole - avoid.
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).
Stoffwechsel
Regorafenib is metabolised by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively). Approximately 90% of the radioactive dose was recovered within 12 days after administration, with about 71% of the dose excreted in faeces (47% as parent compound, 24% as metabolites), and about 19% of the dose excreted in urine as glucuronides. Urinary excretion of glucuronides decreased below 10% under steady-state conditions. Parent compound found in faeces could be derived from intestinal degradation of glucuronides or reduction of metabolite M-2 (N-oxide), as well as unabsorbed regorafenib.
Einzelnachweise
[1]. wilhelm sm, dumas j, adnane l, et al. regorafenib (bay 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. int j cancer, 2011, 129(1): 245-255.
[2]. schmieder r, hoffmann j, becker m, et al. regorafenib (bay 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. int j cancer, 2014, 135(6): 1487-1496.

Regorafenib Upstream-Materialien And Downstream Produkte

Regorafenib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

755037-03-7, Regorafenib Verwandte Suche:

Send Inquriy