755037-03-7 Usage
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
Different sources of media describe the Description of 755037-03-7 differently. You can refer to the following data:
1. 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.
2. 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.
Uses
Different sources of media describe the Uses of 755037-03-7 differently. You can refer to the following data:
1. It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent.
2. BAY 73-4506 (Regorafenib) is a multikinase inhibitor with IC50 of 17, 40 and 69 nM c-KIT, VEGFR2, B-Raf.
3. 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.
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
Interrupted aza-Wittig reactions using iminophosphoranes to synthesize 11C-carbonyls
Ismailani, Uzair S.,Munch, Maxime,Mair, Braeden A.,Rotstein, Benjamin H.
supporting information, p. 5266 - 5269 (2021/06/06)
A direct CO2-fixation methodology couples structurally diverse iminophosphoranes with various nucleophiles to synthesize ureas, carbamates, thiocarbamates, and amides, and is amenable for 11C radiolabeling. This methodology is practical, as demonstrated by the synthesis of >35 products and isolation of the molecular imaging radiopharmaceuticals [11C]URB694 and [11C]glibenclamide. This journal is
Synthesis method of regorafenib
-
, (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.
Direct conversion of carboxylic acids to various nitrogen-containing compounds in the one-pot exploiting curtius rearrangement
Kumar, Arun,Kumar, Naveen,Sharma, Ritika,Bhargava, Gaurav,Mahajan, Dinesh
, p. 11323 - 11334 (2019/09/10)
Herein we report, a single-pot multistep conversion of inactivated carboxylic acids to various N-containing compounds using a common synthetic methodology. The developed methodology rendered the use of carboxylic acids as a direct surrogate of primary amines, for the synthesis of primary ureas, secondary/tertiary ureas, O/S-carbamates, benzoyl ureas, amides, and N-formyls, exploiting the Curtius reaction. This approach has a potential to provide a diversified library of N-containing compounds, starting from a single carboxylic acid, based on the selection of the nucleophile.
