Product Name: Regorafenib

Synonyms: Regorafenib;BAY 73-4506;4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide;BAY 73-4506(Regorafenib);4-(4-(3-(4-chloro-3-(trifluoroMethyl)phenyl)ureido)-3-fluorophenoxy)-N-MethylpicolinaMide;4-[4-({[4-chioro-3-(trifluoroMethyl)phenyl]carbaMoyl}aMino)-3-fluorophenoxy]-pyridine-2-carboxylic acid MethylaMide;REGORAFENIB BAY 73-4506 BAYER HEALTHCARE (SEE ALSO COLORECTAL, LUNG, STOMACH) PHASE II(REGORAFENIB) PHARMACEUTICALS (888) 842-2937WAYNE, NJ;Regorafenib (BAY 73-4506)

CAS: 755037-03-7

MF: C21H15ClF4N4O3

MW: 482.82

EINECS: 815-051-1

Product Categories: Inhibitors;API;Amines;Aromatics;Heterocycles;Anti-cancer&immunity;Intermediates & Fine Chemicals;Pharmaceuticals

Mol File: 755037-03-7.mol

Regorafenib Structure

Regorafenib Chemical Properties

Melting point 206.0 to 210.0 °C

Boiling point 513.4±50.0 °C(Predicted)

density 1.491±0.06 g/cm3(Predicted)

form White powder.

pka 12.04±0.70(Predicted)

CAS DataBase Reference 755037-03-7

Safety Information

HS Code 29242990

MSDS Information

Regorafenib Usage And Synthesis

Side effects

Regorafenib is being approved with a Boxed Warning alerting patients and health care professionals that severe and fatal liver toxicity occurred in patients treated with regorafenib during clinical studies. Serious side effects, which occurred in less than one percent of patients, were liver damage, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks and perforations (holes) in the intestines. The most common side effects reported in patients treated with regorafenib include weakness or fatigue, loss of appetite, hand-foot syndrome (also called palmar-plantar erythrodysesthesia), diarrhoea, mouth sores (mucositis), weight loss, infection, high blood pressure, and changes in voice volume or quality (dysphonia).

Small Molecule Inhibitor

Regorafenib (BAY 73-4506, Stivarga ) is a new oral small molecule multi-kinases inhibitor. It can inhibit the target kinases associated with angiogenesis and tumorigenesis. The pathway influenced by regorafenib and the biomarkers for monitoring the efficacy of regorafenib become hot spots. Because of its wide spectrum kinase inhibitory activity, the utilization of regorafenib in many clinical indications are also carried out extensively. Since regorafenib is approved with the box warning, its side effects can not be ignored.

FDA Approve

Regorafenib (BAY73-4506) is a new type of multikinase inhibitor developed by Bayer, and is the first small molecule kinase inhibitor approved by the U.S. FDA on September 27, 2012 used for fast track colorectal cancer that develops and metastases after conventional treatment. 

Regorafenib achieves good results in some patients with rectal cancer that are resistant to traditional chemotherapy, but not all rectal cancers are sensitive to it. Therefore, the pathway influenced by regorafenib and the biomarkers for monitoring the efficacy of regorafenib become hot spots.

Description 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.

Description 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)

Uses It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent.

Uses BAY 73-4506 (Regorafenib) is a multikinase inhibitor with IC50 of 17, 40 and 69 nM c-KIT, VEGFR2, B-Raf.

Uses 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.

Brand name Stivarga

Clinical Use

Treatment of colorectal cancer and gastrointestinal stromal tumours

Treatment of hepatocellular carcinoma

Drug interactions 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).

Metabolism 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.