Chemical Properties
White Solid
Uses
Enzalutamide (MDV3100) is an androgen-receptor (AR) antagonist with IC50 of 36 nM
Uses
MDV 3100 is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. MDV 3100 has also been shown to induce tumor cell apoptosis, and has no agonist activity. MDV 3100 is a candidate for the treatment of castration-resistant prostate cancer.
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.
Description
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.
Originator
University of California (United States)
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.
Synthesis
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.
Drug interactions
Potentially hazardous interactions with other drugs
Anticoagulants: possibly reduces concentration effect
of coumarinsAnxiolytics: concentration of midazolam reduced.Cytotoxics: concentration of palbociclib possibly
reduced - avoid. Lipid-regulating drugs: concentration increased by
gemfibrozil - avoid or halve enzalutamide dose.
Metabolism
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
CYP2C8Excreted mainly as metabolites 71% in urine and 14% via
faeces.
References
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
