1195765-45-7 Usage
Description
Different sources of media describe the Description of 1195765-45-7 differently. You can refer to the following data:
1. N-[3-[5-(2-Amino-4-pyrimidinyl)-2-(tert-butyl)-4-thiazolyl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide is well known as dabrafenib. It is a drug for the treatment of cancers associated with a mutated version of the gene BRAF. Dabrafenib acts as an inhibitor of the associated enzyme B-Raf, which plays a role in the regulation of cell growth. Dabrafenib has clinical activity with a manageable safety profile in clinical trials of phase-I and -II in patients with BRAF(V600)-mutated metastatic melanoma1,2. Its mechanism of action is acted as a Protein Kinase Inhibitor, and Cytochrome P450 3A4 Inducer, and Cytochrome P450 2B6 Inducer, and Cytochrome P450 2C8 Inducer, and Cytochrome P450 2C9 Inducer, and Cytochrome P450 2C19 Inducer, and Organic Anion Transporting Polypeptide 1B1 Inhibitor, and Organic Anion Transporting Polypeptide 1B3 Inhibitor, and Organic Anion Transporter 1 Inhibitor, and Organic Anion Transporter 3 Inhibitor, and Breast Cancer Resistance Protein Inhibitor3,4. It is not indicated for the treatment of patients with wild-type BRAF melanoma or wild-type BRAF NSCLC. MEKINIST is not indicated for the treatment of patients with melanoma who have progressed on prior BRAF-inhibitor therapy5.
2. In May 2013, the US FDA approved dabrafenib (also referred to as GSK 2118436) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by a FDA-approved test. Dabrafenib was identified from a screen of an oncology-directed kinase collection, followed by extensive structure–activity relationships (SAR) on an initial thiazole lead. Dabrafenib is a potent inhibitor of B-BRAFV600E kinase (IC50=0.65 nM) compared to its potency against wild-type B-raf (IC50=3.2 nM). It also inhibits other kinases (e.g., CRAF) and other mutant B-raf kinases (BRAFV600E and BRAFV600D) with enzyme IC50s of <5 nM and is fairly selective versus a panel of 270 kinases. Consistent with its in vitro activity, oral administration of dabrafenib inhibits the growth of B-RafV600E mutant melanoma (A375P) and colon cancer (Colo205) human tumor xenografts growing subcutaneously in immunocompromised mice. Key steps in the synthesis of dabrafenib are condensation of an aryl sulfonamide ester with the lithium anion of 2-chloro-4-methylpyrimidine to generate a ketone intermediate and bromination of the ketone intermediate with N-bromosuccinamide followed by cyclization with tert-butyl thioamide to afford the desired thiazole core.
Synthetic Methods
The key step in the synthesis of Dabrafenib is the construction of the 1,3-thiazole ring, which is usually carried out by the closing ring directly of thioamide (as a 1,3-binuclear reagent) and anα-carbonyl halide (as a 1,2-amphiphilic reagent). Sulfonyl chloride 1 and aniline 2 gave sulfonamide 3 under basic conditions. Methyl pyrimidine 4 with non-nucleophilic strong alkali LiHMDS pull out the acid proton on the methyl and react with 3 to obtain 5, and the latter has α-bromination with NBS to obtain 1,2-amphiphilic reagent 6, and then 6 reacts with 1 , 3-parent nucleotides 7 to close the ring to obtain 8, and finally reacts with ammonia to obtain Dabrafenib.
Figure 1: synthetic route of Dabrafenib
Biological activity
Dabrafenib (GSK2118436) is a mutant BRAFV600 specific inhibitor with an IC50 of 0.8 nM, and effects for B-Raf (wt) and c-Raf is 4 and 6 fold lower respectively.
How to use
It is usually taken twice a day on an empty stomach, 1 hour before or 2 hours after a meal. Take dabrafenib about 12 hours apart at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Do not stop taking dabrafenib without talking to your doctor.
Swallow the capsules whole; do not split, chew, or crush them.
Your doctor may adjust your dose of dabrafenib depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment.
Major Side Effects
The following side effects are common (occurring in greater than 30%) for patients taking dabrafenib :
Hyperglycemia
Hyperkeratosis
Hypophosphatemia
Headache
These side effects are less common side effects (occurring in about 10-29%) of patients receiving dabrafenib:
Fever
Joint pain
Papilloma (warts/growths)
Hair loss
Hand-foot syndrome (Palmar-planter erythrodyesthesia)
Increased Alkaline phosphatase
Rash
Back pain
Cough
Muscle aches
Constipation
Nasopharyngitis
In vitro
Dabrafenib is selective for Raf kinases and is 400 times more active against B-Raf than other tested 91% kinases. Dabrafenib inhibits B-RafV600E kinase, resulting in reduced phosphorylation of ERK and inhibition of cell proliferation. The cells stagnate in the G1 phase in cancer cells that specifically encode mutated B-RafV600E.
In vivo
Dabrafenib (oral) inhibits the growth of B-RafV600E mutated melanoma (A375P). Dabrafenib (oral) also inhibits tumor growth, subcutaneously injecting colon cancer (Colo205) in immunocompromised mice.
References
Different sources of media describe the References of 1195765-45-7 differently. You can refer to the following data:
1. https://www.caymanchem.com/product/16989
https://en.wikipedia.org/wiki/Dabrafenib
https://pubchem.ncbi.nlm.nih.gov/compound/Dabrafenib
Menzies, A. M., and G. V. Long. "Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma. " Clinical Cancer Research 20.8(2014): 2035-2043.
https://www.hcp.novartis.com/products/tafinlar-mekinist/
2. 1) Huang?et al. (2013),?B-Raf and the inhibitors: from bench to bedside; J. Hematol. Oncol.,?6?1
2) Ji?et al. (2016),?Endoplasmic reticulum stress-induced autophagy determines the susceptibility of melanoma cells to dabrafenib; Drugs Des. Dev. Ther.?10?2491
3) Herr?et al.?(2015),?B-Raf inhibitors induce epithelial differentiation in BRAF-mutant colorectal cancer cells; Cancer Res.,?75?216
Originator
GlaxoSmithKline (United States)
Uses
Dabrafenib is an inhibitor of mutated BRAF kinase and has clinical activity with a manageable safety profile in clinical trials of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma.
Definition
ChEBI: An organofluorine compound and antineoplastic agent, used as its mesylate salt in treatment of metastatic melanoma.
Brand name
Tafinlar
Clinical Use
Selective inhibitor of BRAF-kinase:Treatment of metastatic melanoma and advanced
non-small cell lung cancer with a BRAF V600
mutation
Drug interactions
Potentially hazardous interactions with other drugs Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis. Oestrogens and progestogens: possibly reduced
contraceptive effect.
Metabolism
Metabolism is mainly by CYP2C8 and CYP3A4
isoenzymes to form hydroxy-dabrafenib, which is further
oxidised via CYP3A4 to form carboxy-dabrafenib.
Carboxy-dabrafenib can be decarboxylated via a nonenzymatic process to form desmethyl-dabrafenib.
Carboxy-dabrafenib is excreted in bile and urine.
Desmethyl-dabrafenib may also be formed in the gut
and reabsorbed. Desmethyl-dabrafenib is metabolised
by CYP3A4 to oxidative metabolites. Both hydroxyand desmethyl-dabrafenib are likely to contribute to
the clinical activity of dabrafenib while the activity of
carboxy-darafenib is not likely to be significant.
Check Digit Verification of cas no
The CAS Registry Mumber 1195765-45-7 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,1,9,5,7,6 and 5 respectively; the second part has 2 digits, 4 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 1195765-45:
(9*1)+(8*1)+(7*9)+(6*5)+(5*7)+(4*6)+(3*5)+(2*4)+(1*5)=197
197 % 10 = 7
So 1195765-45-7 is a valid CAS Registry Number.
1195765-45-7Relevant articles and documents
C2-Selective, Functional-Group-Divergent Amination of Pyrimidines by Enthalpy-Controlled Nucleophilic Functionalization
Ham, Won Seok,Choi, Hoonchul,Zhang, Jianbo,Kim, Dongwook,Chang, Sukbok
, p. 2885 - 2892 (2022/02/23)
Synthesis of heteroaryl amines has been an important topic in organic chemistry because of their importance in small-molecule discovery. In particular, 2-Aminopyrimidines represent a highly privileged structural motif that is prevalent in bioactive molecules, but a general strategy to introduce the pyrimidine C2-N bonds via direct functionalization is elusive. Here we describe a synthetic platform for site-selective C-H functionalization that affords pyrimidinyl iminium salt intermediates, which then can be transformed into various amine products in situ. Mechanism-based reagent design allowed for the C2-selective amination of pyrimidines, opening the new scope of site-selective heteroaryl C-H functionalization. Our method is compatible with a broad range of pyrimidines with sensitive functional groups and can access complex aminopyrimidines with high selectivity.
Sulfonamidation of Aryl and Heteroaryl Halides through Photosensitized Nickel Catalysis
Kim, Taehoon,McCarver, Stefan J.,Lee, Chulbom,MacMillan, David W. C.
, p. 3488 - 3492 (2018/03/05)
Herein we report a highly efficient method for nickel-catalyzed C?N bond formation between sulfonamides and aryl electrophiles. This technology provides generic access to a broad range of N-aryl and N-heteroaryl sulfonamide motifs, which are widely represented in drug discovery. Initial mechanistic studies suggest an energy-transfer mechanism wherein C?N bond reductive elimination occurs from a triplet excited NiII complex. Late-stage sulfonamidation in the synthesis of a pharmacologically relevant structure is also demonstrated.
PHARMACEUTICAL COMBINATION COMPRISING THE PI3K INHIBITOR ALPELISIB AND THE B-RAF INHIBITOR DABRAFENIB; THE USE OF SUCH COMBINATION IN THE TREATMENT OR PREVENTION OF CANCER
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Page/Page column 28; 32, (2017/03/21)
The present disclosure pertains to a pharmaceutical combination comprising (a) alpha- isoform specific PI3K inhibitor and (b) a B-RAF inhibitor; combined preparations and pharmaceutical compositions thereof; the uses of such combination in the treatment or prevention of cancer; and methods of treating or preventing cancer in a subject comprising administering a therapeutically effective amount of such combination.