Enzalutamide

Bezeichnung:Enzalutamide

CAS-Nr915087-33-1

Englisch Name:Enzalutamide

CBNumberCB62500946

SummenformelC21H16F4N4O2S

Molgewicht464.44

MOL-Datei915087-33-1.mol

Enzalutamide physikalisch-chemischer Eigenschaften

Schmelzpunkt	198 - 200°C
Dichte	1.49
storage temp.	-20°C
Löslichkeit	Soluble in DMSO (>25 mg/ml)
Aggregatzustand	solid
pka	13.88±0.46(Predicted)
Farbe	White to off-white
Stabilität	Stable for 1 year as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
InChI	InChI=1S/C21H16F4N4O2S/c1-20(2)18(31)28(12-5-4-11(10-26)15(8-12)21(23,24)25)19(32)29(20)13-6-7-14(16(22)9-13)17(30)27-3/h4-9H,1-3H3,(H,27,30)
InChIKey	WXCXUHSOUPDCQV-UHFFFAOYSA-N
SMILES	C(NC)(=O)C1=CC=C(N2C(=S)N(C3=CC=C(C#N)C(C(F)(F)F)=C3)C(=O)C2(C)C)C=C1F

Sicherheit

HS Code

29339900

Gefahreninformationscode (GHS)

Enzalutamide Chemische Eigenschaften,Einsatz,Produktion Methoden

Beschreibung
In August 2012, the US FDA approved enzalutamide for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients who have previously been treated with docetaxel. Synthesis of enzalutamide was achieved by a triply convergent route that employed a Strecker condensation, followed by isothiocyanate condensation and hydrolysis to form the thiohydantoin moiety. In LNCaP/AR cells with high expression of AR, enzalutamide demonstrated potent inhibition of 16b-[18F]-5α-dihydrotestosterone binding (IC₅₀=21 nM compared with bicalutamide IC₅₀=160 nM), and inhibited AR translocation to the nucleus more potently than bicalutamide.The primary metabolite is the result of CYP2C8-mediated N-demethylation; enzalutamide is primarily eliminated by hepatic metabolism.
Chemische Eigenschaften
White Solid
Originator
University of California (United States)
Verwenden
MDV3100, known as Enzalutamide, is a second-generation androgen receptor (AR) signaling inhibitor. It is able to inhibit binding of androgens to the AR, AR nuclear translocation, and the association of the AR with DNA.
Definition
ChEBI: A benzamide obtained by formal condensation of the carboxy group of 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl}-2-fluorobenzoic acid with methylamine. Used for the treatment of of metastatic castration-resistant p ostate cancer.
Trademarks
Xtandi
Clinical Use
In August 2012, the FDA approved enzalutamide, marketed by Medivation and Astellas Pharma US for the treatment of metastatic castration-resistant prostate cancer (CRPC), specifically for those patients who had previously received docetaxel. Enzalutamide is an inhibitor of androgen receptors (AR)— whose increased expression has been closely linked with castration-resistant prostate cancer (CRPC),thus, AR inhibitors have seen increased recent attention from the medicinal chemistry community. Phase I/II trials were particularly promising for enzalutamide, as 43% of patients showed >50% sustained suppression of a key serum biomarker.
Synthese
Of the several patents and papers describing synthetic approaches, a 2011 patent represents the most likely scale production route to enzalutamide, and this is described in the scheme.Commercially available carboxylic acid 70 was first converted to the corresponding acid chloride 71, followed by amide formation with methylamine to furnish benzamide 72 in 90% yield over two steps. Bromide 72 was then coupled with amine 73 using copper (I) catalysis to afford trisubstituted benzene 74 in 76% isolated yield. Esterification of 74 to 75 with iodomethane furnished one fragment for the key ring-forming event. Isothiocyanate 76, available in one step from the corresponding aniline 77, was then exposed to aminoester 75 in the presence of warm isopropyl acetate, resulting in construction of the lynchpin thiohydantoin and delivering enzalutamide (XI) in an impressive 78% yield. This 5-step process has successfully generated multi-gram quantities of the drug in 50.7% overall yield.
target
Androgen-receptor
Arzneimittelwechselwirkung
Potentially hazardous interactions with other drugs Anticoagulants: possibly reduces concentration effect of coumarins
Anxiolytics: concentration of midazolam reduced.
Cytotoxics: concentration of palbociclib possibly reduced - avoid.
Lipid-regulating drugs: concentration increased by gemfibrozil - avoid or halve enzalutamide dose.
Stoffwechsel
Clearance of enzalutamide is mainly via hepatic metabolism, producing an active metabolite that is equally as active as enzalutamide and circulates at approximately the same plasma concentration as enzalutamide. Under conditions of clinical use, enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and CYP2C19, and has no clinically relevant effect on CYP2C8
Excreted mainly as metabolites 71% in urine and 14% via faeces.
Einzelnachweise
Tran et al. (2009), Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer; Science 324 787 Jung et al. (2010), Structure-Activity Relationship for Thiohydantoin Androgen Receptor Antagonist for Castration-Resistant Prostate Cancer (CRPC); J. Med. Chem. 53 2779

Enzalutamide Upstream-Materialien And Downstream Produkte

Enzalutamide Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

915087-33-1, Enzalutamide Verwandte Suche:

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