ENZALUTAMIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H16F4N4O2S
Molecular Weight	464.436
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CNC(=O)C1=C(F)C=C(C=C1)N2C(=S)N(C(=O)C2(C)C)C3=CC(=C(C=C3)C#N)C(F)(F)F

InChI

InChIKey=WXCXUHSOUPDCQV-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C21H16F4N4O2S
Molecular Weight	464.436
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Enzalutamide (brand name Xtandi) is an orally bioavailable, organic, non-steroidal small molecule targeting the androgen receptor (AR) with potential antineoplastic activity. It was developed at UCLA and marketed by the pharmaceutical company Medivation for the treatment of metastatic castration-resistant prostate cancer. Through a mechanism that is reported to be different from other approved AR antagonists, enzalutamide inhibits the activity of prostate cancer cell ARs, which may result in a reduction in prostate cancer cell proliferation and, correspondingly, a reduction in the serum prostate specific antigen (PSA) level. AR over-expression in prostate cancer represents a key mechanism associated with prostate cancer hormone resistance.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Androgen Receptor 169	Inhibitor 8,504		21.4 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Castrate-resistant prostate cancer 20	Primary		Approved 8,583	XTANDI

C_max

Value	Dose	Analyte	Population
16.59 μg/mL	160 mg 1 times / day multiple, oral	ENZALUTAMIDE plasma	Homo sapiens
6.48 μg/mL	160 mg single, oral	ENZALUTAMIDE plasma	Homo sapiens
3.4 μg/mL	150 mg single, oral	ENZALUTAMIDE plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
321.5 μg × h/mL	160 mg 1 times / day multiple, oral	ENZALUTAMIDE plasma	Homo sapiens
368 μg × h/mL	160 mg single, oral	ENZALUTAMIDE plasma	Homo sapiens
340 μg × h/mL	150 mg single, oral	ENZALUTAMIDE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
90.7 h	160 mg single, oral		ENZALUTAMIDE plasma	Homo sapiens
6 day	150 mg single, oral		ENZALUTAMIDE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
1.94%	150 mg single, oral		ENZALUTAMIDE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
300 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 68 years (range: 44–93 years )	DLT: Rash...
300 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 68 years (range: 44–93 years )	DLT: Seizure...
300 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 68 years (range: 44–93 years )	Other AEs: Convulsions...
240 mg 1 times / day multiple, oral MTD	unhealthy, 68 years (range: 44–93 years )	Disc. AE: Fatigue... Other AEs: Fatigue...
240 mg 2 times / day multiple, oral	unhealthy, 68 years (range: 44–93 years )	DLT: Seizure...

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AEs

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AE	Significance	Dose	Population
Rash	33% DLT, Disc. AE	300 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 68 years (range: 44–93 years )
Seizure	33% DLT, Disc. AE	300 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 68 years (range: 44–93 years )
Convulsions	grade 3-4, 33%	300 mg 2 times / day multiple, oral Highest studied dose	unhealthy, 68 years (range: 44–93 years )
Fatigue	3% Disc. AE	240 mg 1 times / day multiple, oral MTD	unhealthy, 68 years (range: 44–93 years )
Fatigue	grade 3-4, 17%	240 mg 1 times / day multiple, oral MTD	unhealthy, 68 years (range: 44–93 years )

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946 inducer 1,087	inhibitor 2,438 inducer 440 substrate 1,193	inhibitor 2,507 substrate 1,388	inhibitor 2,217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 926 CYP2C8 1,057 CYP2C19 2,057 CYP3A4/5 296 CYP1A2 2,153 P-gp 1,741	CYP2C8 810 P-gp 2,052 CYP3A5 446 CYP1A1 389 CYP1A2 1,197 CYP2A6 626 CYP2B6 776 CYP2C18 149 CYP2C19 1,119 CYP2E1 729	CYP2C19 329 CYP2C8 198

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
CYP2C19 2,141	inducer 1,966	moderate
CYP2C9 2,497	inducer 1,966	moderate
CYP3A4 2,633	inducer 1,966	strong	yes (co-administration study)
P-gp 1,932	inhibitor 4,027	yes [IC50 1.67 uM]
CYP2C8 1,117	inhibitor 4,027	yes [IC50 10 uM]	no (co-administration study)

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Drug as victim

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Target	Modality	Activity
CYP1A1 389	substrate 4,014	no
CYP1A2 1,197	substrate 4,014	no
CYP2A6 626	substrate 4,014	no
CYP2B6 776	substrate 4,014	no
CYP2C18 149	substrate 4,014	no

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2,263	inhibitor 2,237

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:68534	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:68534
ChemicalBook	CB62500946	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62500946
eMolecules	32176540	https://www.emolecules.com/cgi-bin/more?vid=32176540
MolPort	MolPort-009-679-470	https://www.molport.com/shop/molecule-link/MolPort-009-679-470
Selleck Chemicals	MDV3100	http://www.selleckchem.com/products/MDV3100.html

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PubMed

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Title	Date	PubMed
Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation.	2013	23704919
Enzalutamide in metastatic prostate cancer before chemotherapy.	2014 Jul 31	24881730
Molecular alterations and emerging targets in castration resistant prostate cancer.	2014 Mar	24418724
Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies.	2015 Jul 13	25908785

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Patents

Sample Use Guides

In Vivo Use Guide

160 mg (four 40 mg capsules) administered orally once daily

Route of Administration: Oral

In Vitro Use Guide

Resistant cells were maintained in vitro under constant exposure to 10 μM of enzalutamide.

Substance Class	Chemical
Record UNII	93T0T9GKNU
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ENZALUTAMIDE

Official Name

English

BENZAMIDE, 4-(3-(4-CYANO-3-(TRIFLUOROMETHYL)PHENYL)-5,5-DIMETHYL-4-OXO-2-THIOXO-1-IMIDAZOLIDINYL)-2-FLUORO-N-METHYL-

Preferred Name

English

ENZALUTAMIDE [USAN]

Common Name

English

4-(3-(4-CYANO-3-(TRIFLUOROMETHYL)PHENYL)-5,5-DIMETHYL-4-OXO-2-THIOXOIMIDAZOLIDIN-1-YL)-2-FLUORO-N-METHYLBENZAMIDE

Systematic Name

English

Enzalutamide [WHO-DD]

Common Name

English

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Classification Tree

Code System

Code

Anti-Androgen

NCI_THESAURUS

C146993

Established Pharmacologic Class

NDF-RT

N0000175560

Prostate cancer

LIVERTOX

NBK548070

Anti-androgens

WHO-ATC

L02BB04

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Code System

Code

Type

Description

IUPHAR

6812

PRIMARY

PUBCHEM

15951529

PRIMARY

WIKIPEDIA

Enzalutamide

PRIMARY

EPA CompTox

DTXSID10912307

PRIMARY

FDA UNII

93T0T9GKNU

PRIMARY

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Related Record

Type

Details


					081I12ZA58

CYTOCHROME P450 2C19

METABOLIC ENZYME -> INDUCER

Comments:

Therefore, co-administration of enzalutamide with CYP3A4, 2C9, and 2C19 substrates with a narrow therapeutic index should be avoided.

Interaction Type:

MODERATE


					2IA57U2YZZ

ANDROGEN RECEPTOR F876L

TARGET -> INHIBITOR RESISTANT


					22ES734693

MULTIDRUG RESISTANCE PROTEIN 1

TRANSPORTER -> INHIBITOR


					PUO0521HZV

CYTOCHROME P450 3A4

METABOLIC ENZYME -> INHIBITOR


					3OKI556HC2

DEUTENZALUTAMIDE

LABELED -> NON-LABELED

Amount:

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Related Record

Type

Details


					5MK9M4BF22

4-(3-(4-CYANO-3-(TRIFLUOROMETHYL)PHENYL)-5,5-DIMETHYL-2,4-DIOXO-1-IMIDAZOLIDINYL)-2-FLUOROBENZOIC ACID

METABOLITE -> PARENT

Interaction Type:

MINOR

Qualification:

URINE

Amount:


					YF8MAL2HDY

ENZALUTAMIDE CARBOXYLIC ACID

METABOLITE INACTIVE -> PARENT

Comments:

In plasma, M1 accounted for 10% of the 14C-radioactivity. In urine, the most abundant 14C-component was M1 (62.7% of dose). In feces, the most abundant 14C-components were M1 and M10, which accounted for 3.34% and 4.26% of the radioactive dose, respectively.

Qualification:

FECAL; PLASMA; URINE


					DTM3GJC5NY

4-(3-(4-CARBAMOYL-3-(TRIFLUOROMETHYL)PHENYL)-5,5-DIMETHYL-4-OXO-2-THIOXO-IMIDAZOLIDIN-1-YL)-2-FLUORO-BENZOIC ACID

METABOLITE -> PARENT

Comments:

In urine, M10 was a minor metabolite, which accounted for 0.67% of the dose. In feces, M10 was one of the most abundant 14C-components, and it accounted for 4.26% of the radioactive dose.

Qualification:

FECAL; URINE


					HZ7ZZC4TC6

4-(3-(4-(AMINOCARBONYL)-3-(TRIFLUOROMETHYL)PHENYL)-5,5-DIMETHYL-4-OXO-2-THIOXO-1-IMIDAZOLIDINYL)-2-FLUORO-N-METHYLBENZAMIDE

METABOLITE -> PARENT

Comments:

Metabolite M7 was trace component in plasma; accounting for ? 2% of the radioactivity in the 6- and 24-hour postdose plasma samples and not detected at any other time point. In urine, M7 accounted for 9.45% of the radioactive dose. In feces, M7 accounted for 1.12% of the radioactive dose.

Qualification:

FECAL; PLASMA; URINE


					KLY798P76T

BENZAMIDE, 4-(3-(4-CYANO-3-(TRIFLUOROMETHYL)PHENYL)-5,5-DIMETHYL-4-OXO-2-THIOXO-1-IMIDAZOLIDINYL)-2-FLUORO-N-(HYDROXYMETHYL)-

METABOLITE -> PARENT

Comments:

Trace amount of M6 was observed in urine (? 0.42% of the dose) and plasma (? 2% of the radioactivity in the 6- and 24-hour postdose plasma samples and not detected at any other time point).

Interaction Type:

MINOR

Qualification:

PLASMA; URINE

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Related Record

Type

Details


					DL8DJ99XBS

4-(3-(1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile

IMPURITY -> PARENT

Amount:


					2CQV7V48AN

N-[3-Fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine methyl ester

IMPURITY -> PARENT

Amount:


					74K9JK886T

DEFLUORO ENZALUTAMIDE

IMPURITY -> PARENT

Amount:


					Q6F84UZ2HZ

O-METHYL (4-CYANO-3-(TRIFLUOROMETHYL)PHENYL)CARBAMOTHIOATE

IMPURITY -> PARENT

Amount:


					HP6388MX6K

4-ISOTHIOCYANATO-2-(TRIFLUOROMETHYL)BENZONITRILE

IMPURITY -> PARENT

Amount:

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Related Record

Type

Details


					93T0T9GKNU

ENZALUTAMIDE

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
Biological Half-life	PHARMACOKINETIC	5.8 days [2.8 to 10.2] (average)	SINGLE ORAL DOSE 160 mg (average)

Tmax	PHARMACOKINETIC	1 hours [0.5 to 3] (average)	DOSE 160 mg (average) ORAL ADMINISTRATION

Volume of Distribution	PHARMACOKINETIC	1.57 Liters/Kilogram (average)

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator