755037-03-7 Usage
Description
Regorafenib, also known as BAY 73-4506 and marketed under the brand name Stivarga, is an orally bioavailable multi-kinase inhibitor with potent anticancer activity. It was approved by the US FDA in September 2012 for the treatment of patients with metastatic colorectal cancer (CRC) who have previously received chemotherapy, anti-EGFR, or anti-VEGF therapy. Regorafenib is a fluorinated analog of sorafenib and is synthesized in two steps from commercially available starting materials. It inhibits various kinases, including RET, C-RAF, VEGFR2, c-Kit, VEGFR1, PDGFRβ, B-RAF, VEGFR3, FGFR, and Tie2, with varying IC50 values.
Uses
1. Used in Oncology:
Regorafenib is used as an anti-cancer agent for the treatment of metastatic colorectal cancer in patients who have previously received chemotherapy, anti-EGFR, or anti-VEGF therapy. It inhibits multiple kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET, and Raf-1, which are involved in tumor growth, angiogenesis, and proliferation.
2. Used in Advanced Gastrointestinal Stromal Tumors (GIST) Treatment:
Regorafenib is used as an anti-proliferative agent for the treatment of advanced gastrointestinal stromal tumors, as it inhibits the activity of PDGFR tyrosine kinase and other relevant kinases.
3. Used in Inflammation Treatment:
Regorafenib is used as an anti-inflammatory agent due to its multikinase inhibitory properties, which can help in reducing inflammation associated with various conditions.
4. Used in Drug Delivery Systems:
Regorafenib can be incorporated into drug delivery systems to improve its bioavailability, delivery, and therapeutic outcomes in cancer treatment. This application can be particularly useful in enhancing the efficacy of regorafenib against cancer cells and overcoming potential limitations of the drug.
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.
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.
references
[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.
Check Digit Verification of cas no
The CAS Registry Mumber 755037-03-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 7,5,5,0,3 and 7 respectively; the second part has 2 digits, 0 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 755037-03:
(8*7)+(7*5)+(6*5)+(5*0)+(4*3)+(3*7)+(2*0)+(1*3)=157
157 % 10 = 7
So 755037-03-7 is a valid CAS Registry Number.
755037-03-7Relevant articles and documents
Synthesis method of regorafenib
-
Paragraph 0029-0031, (2021/04/21)
The invention provides a synthesis method of regorafenib, which adopts 3-fluoro-4-nitrophenol as a raw material to replace the traditional 3-fluoro-4-aminophenol to carry out etherification reaction, and then carries out catalytic hydrogenation to obtain 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide, and has the advantages that the nitro stability is much higher than the amino stability; catalytic hydrogenation is carried out after etherification with the 4-chloro-2-pyridine formamide, such that the hydroxyl group is etherified so that the product stability is improved greatly, the purity and the yield of the product obtained after the catalytic hydrogenation are substantially improved, and the quality of the final product regorafenib is ensured. 3-fluorine-4-nitrophenol is used as a starting material to be subjected to etherification reaction with 4-chlorine-2-pyridine formamide, so that 4-methyl-2-pentanone is not needed to protect amino, and the quality of an intermediate obtained after catalytic hydrogenation and the quality of a final product are better.
Preparation method of regorafenib
-
Paragraph 0025-0040, (2021/05/29)
The invention relates to a preparation method of regorafenib. The method comprises the following steps: adding 4-chloro-3-trifluoromethylaniline and an alkaline reagent into an organic solvent of triphosgene, and stirring for reaction to obtain a compound 2; and then adding N-methyl-4-(4-amino-3-fluoro) phenoxy pyridine-2-formamide and an alkaline reagent into the organic solvent of the compound 2, and reacting to obtain the regorafenib. The method provided by the invention is short in reaction time, easy for large-scale preparation, easy to operate, good in stability, high in purity and yield, free of intermediate separation and suitable for industrial production.
Two novel platinum(II) complexes with sorafenib and regorafenib: Synthesis, structural characterization, and evaluation of in vitro antitumor activity
Qin, Qi-Pin,Wang, Zhen-Feng,Tan, Ming-Xiong,Wang, Shu-Long,Zou, Bi-Qun,Luo, Dong-Mei,Qin, Jiao-Lan,Zhang, Shu-Hua
, p. 27 - 30 (2019/04/03)
Two new Pt(II) complexes with sorafenib (SRFN) and regorafenib (RGFN), having the general formulae [Pt(SRFN)(DMSO)Cl2] (SRFN-Pt) and [Pt(RGFN)(DMSO)Cl2] (RGFN-Pt), were prepared and characterized by ESI-MS, IR, UV–Vis spectroscopy, elemental analyses, and 1H and 13C NMR, respectively. The anticancer activities of SRFN-Pt and RGFN-Pt were evaluated by MTT assay with NCI-H460 (human non-small cell lung cancer NCI-H460 cell line), SK-OV-3 (ovarian cancer cell line), SK-OV-3/DDP (cisplatin-resistant SK-OV-3 cell line), T-24 (human bladder cancer cell line), HeLa (cervical cancer cell line), A549/DDP (cisplatin-resistant A549/DDP non-small cell lung cancer cell line) cancer cells and in the normal HL-7702 cells. The results suggested that SRFN-Pt and RGFN-Pt were more effective against the A549/DDP tumor cells (IC50 = 1.18 ± 0.15 μM and 0.13 ± 0.03 μM) than SRFN (45.03 ± 0.79 μM), RGFN (40.11 ± 2.15 μM), and cisplatin (97.63 ± 1.06 μM), respectively, and RGFN-Pt was more effective than SRFN-Pt. In addition, SRFN-Pt and RGFN-Pt induced G2/M and S phase arrest. Cytotoxic mechanism studies revealed that SRFN-Pt and RGFN-Pt triggered mitochondria-mediated apoptotic cell death at low concentration. RGFN-Pt exhibited obvious priority on the in vitro antitumor activity than SRFN-Pt, which should be undoubtedly correlated with the key roles of the fluoro substituted groups in the RGFN ligand of RGFN-Pt. The in vitro anti-tumor activity studies suggested that RGFN-Pt pointed to a new direction in developing Pt(II) drugs as anti-cancer agent.