Dabrafenib

Bezeichnung:Dabrafenib

CAS-Nr1195765-45-7

Englisch Name:Dabrafenib

CBNumberCB32604230

SummenformelC23H20F3N5O2S2

Molgewicht519.56

MOL-Datei1195765-45-7.mol

Dabrafenib physikalisch-chemischer Eigenschaften

Schmelzpunkt	214-216oC
Siedepunkt	653.7±65.0 °C(Predicted)
Dichte	1.443
storage temp.	-20°C
Löslichkeit	Soluble in DMSO (up to 30 mg/ml with warming), or in Ethanol (up to 1 mg/ml with warming).
Aggregatzustand	White solid.
pka	6.62±0.10(Predicted)
Farbe	Off-white
Stabilität	Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.
InChIKey	BFSMGDJOXZAERB-UHFFFAOYSA-N
SMILES	C1(S(NC2=CC=CC(C3=C(C4C=CN=C(N)N=4)SC(C(C)(C)C)=N3)=C2F)(=O)=O)=C(F)C=CC=C1F

Sicherheit

HS Code

29350090

Gefahreninformationscode (GHS)

Dabrafenib Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
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 BRAF^V600E 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-BRAF^V600E 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 (BRAF^V600E and BRAF^V600D) with enzyme IC_50s 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-Raf^V600E 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.
Originator
GlaxoSmithKline (United States)
Verwenden
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.
Trademarks
Tafinlar
Allgemeine Beschreibung
Class: dual threonine/tyrosine kinase; Treatment: melanoma with BRAF mutations; Oral bioavailability = 95%; Elimination half-life = 8 h; Protein binding = 99.7%
Pharmakokinetik
Dabrafenib exhibits an oral bioavailability of 95%, indicative of extensive absorption and low firstpass intestinal and hepatic metabolism. The excellent oral bioavailability contributes to a much lower dosage than vemurafenib (150 mg, BID vs. 960 mg, BID). It has an elimination half-life of 8 h, resulting in twice-daily dosing regimen. Dabrafenib undergoes metabolism primarily via oxidation of the t-butyl group to form hydroxydabrafenib 6, which is further oxidized to carboxydabrafenib 7. Subsequent decarboxylation furnishes the desmethyl-dabrafenib 8 via a pH-dependent decarboxylation (Fig. 4). The major route of elimination of dabrafenib is a combination of oxidative metabolism (48% of the dose) and biliary excretion.
Clinical Use
Selective inhibitor of BRAF-kinase:
Treatment of metastatic melanoma and advanced non-small cell lung cancer with a BRAF V600 mutation
target
B-Raf (V600E)
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Oestrogens and progestogens: possibly reduced contraceptive effect.
Stoffwechsel
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.
Einzelnachweise
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

Dabrafenib Upstream-Materialien And Downstream Produkte

Dabrafenib Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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