APALUTAMIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H15F4N5O2S
Molecular Weight	477.435
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CNC(=O)C1=CC=C(C=C1F)N2C(=S)N(C(=O)C23CCC3)C4=CC(=C(N=C4)C#N)C(F)(F)F

InChI

InChIKey=HJBWBFZLDZWPHF-UHFFFAOYSA-N

InChI=1S/C21H15F4N5O2S/c1-27-17(31)13-4-3-11(8-15(13)22)30-19(33)29(18(32)20(30)5-2-6-20)12-7-14(21(23,24)25)16(9-26)28-10-12/h3-4,7-8,10H,2,5-6H2,1H3,(H,27,31)

HIDE SMILES / InChI

Molecular Formula	C21H15F4N5O2S
Molecular Weight	477.435
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

Apalutamide (developmental code name ARN-509) is a selective and competitive androgen receptor inhibitor with IC50 of 16 nM, useful for prostate cancer treatment. Apalutamide binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells. Apalutamide is currently in phase III clinical trials for castration-resistant prostate cancer.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Androgen Receptor 167	Antagonist 2,778		16.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Prostate cancer 178	Primary		Approved 8,429	ERLEADA

C_max

Value	Dose	Co-administered	Analyte	Population
6 μg/mL	240 mg 1 times / day steady-state, oral		APALUTAMIDE plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
100 μg × h/mL	240 mg 1 times / day steady-state, oral		APALUTAMIDE plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
72 h	240 mg 1 times / day steady-state, oral		APALUTAMIDE plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
4%	240 mg 1 times / day steady-state, oral		APALUTAMIDE plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
480 mg 1 times / day multiple, oral Highest studied dose	unhealthy, 68 years (range: 45 - 81 yers)
300 mg 1 times / day multiple, oral	unhealthy, 68 years (range: 45 - 81 yers)	DLT: Abdominal pain...
240 mg 1 times / day steady, oral Recommended\|MTD	unhealthy, 74 years (range: 48-97 years)	Disc. AE: Rash, Rash...
240 mg 1 times / day steady, oral Recommended\|MTD	unhealthy, 74 years (range: 48-97 years)	Disc. AE: Fatigue, Decreased appetite...

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AEs

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AE	Significance	Dose	Population
Abdominal pain	grade 3, 1 patient DLT, Disc. AE	300 mg 1 times / day multiple, oral	unhealthy, 68 years (range: 45 - 81 yers)
Rash	3% Disc. AE	240 mg 1 times / day steady, oral Recommended\|MTD	unhealthy, 74 years (range: 48-97 years)
Diarrhea	>1 Disc. AE	240 mg 1 times / day steady, oral Recommended\|MTD	unhealthy, 74 years (range: 48-97 years)
Fatigue	>1 Disc. AE	240 mg 1 times / day steady, oral Recommended\|MTD	unhealthy, 74 years (range: 48-97 years)
Hematuria	>1 Disc. AE	240 mg 1 times / day steady, oral Recommended\|MTD	unhealthy, 74 years (range: 48-97 years)

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737 inducer 781 inhibitor 1,587	inhibitor 1,767		inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 CYP2C19 1,478 CYP2C8 911 P-gp 1,461 BCRP 699 OCT2 647 OAT3 642 MATE1 306 MATE2 263	CYP2C8 693 P-gp 1,537 carboxylesterase 4	CYP2B6 547 P-gp 257 OATP1B1 26 BCRP 75

Drug as perpetrator

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Target	Modality	Activity	Metabolite
OAT3 644	inhibitor 3,277	yes [IC50 12 uM]
MATE1 308	inhibitor 3,277	yes [IC50 13.8 uM]
OCT2 648	inhibitor 3,277	yes [IC50 27.2 uM]
MATE2 263	inhibitor 3,277	yes [IC50 37.9 uM]
OCT2 648	inhibitor 3,277	yes [IC50 4.8 uM]	N-desmethyl apalutamide 1

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP2C8 693	substrate 3,367	major
P-gp 1,537	substrate 3,367	yes
carboxylesterase 4	substrate 3,367	yes
CYP3A4 1,737	substrate 3,367	yes	yes (co-administration study)

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626		N-desmethyl apalutamide 1

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
001 Chemical	DY105300	https://www.001chemical.com/chem/956104-40-8
AA Blocks	AA00IJ5V	https://www.aablocks.com/goods/Goods/detail?id=AA00IJ5V
Aaron Chemicals	AR00IJXN	http://www.aaronchem.com/956104-40-8
abcr GmbH	AB479612	http://www.abcr.com/shop/en/AB479612
AbMole Bioscience	M2270	http://www.abmole.com/products/arn-509.html

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PubMed

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Title	Date	PubMed
ARN-509: a novel antiandrogen for prostate cancer treatment.	2012 Mar 15	22266222
New agents for prostate cancer.	2014 Sep	24658665
Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort.	2016 Dec	27160947

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose of ERLEADA (apalutamide) is 240 mg (four 60 mg tablets) administered orally once daily. Swallow the tablets whole. ERLEADA can be taken with or without food.

Route of Administration: Oral

In Vitro Use Guide

APALUTAMIDE binds AR with IC50 16 nM

Substance Class	Chemical
Record UNII	4T36H88UA7
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

APALUTAMIDE

Official Name

English

APALUTAMIDE [ORANGE BOOK]

Common Name

English

4-(7-(6-CYANO-5-(TRIFLUOROMETHYL)PYRIDIN-3-YL)-8-OXO-6-THIOXO-5,7-DIAZASPIRO(3.4)OCTAN-5-YL)-2-FLUORO-N-METHYLBENZAMIDE

Systematic Name

English

Apalutamide [WHO-DD]

Common Name

English

ERLEADA

Brand Name

English

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Classification Tree

Code System

Code

Anti-androgens

WHO-ATC

L02BB05

Anti-Androgen

NCI_THESAURUS

C146993

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Code System

Code

Type

Description

DRUG BANK

DB11901

PRIMARY

PUBCHEM

24872560

PRIMARY

INN

10118

PRIMARY

DAILYMED

4T36H88UA7

PRIMARY

FDA UNII

4T36H88UA7

PRIMARY

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Related Record

Type

Details


					ZWJ2Y6JZWY

OAT-3

TRANSPORTER -> INHIBITOR

Qualification:

IC50

Amount:

12 MICROMOLAR [11 to 13] (average)


					B46KUN2O9L

MATE-2

TRANSPORTER -> INHIBITOR

Qualification:

IC50

Amount:

37.9 MICROMOLAR [35.3 to 40.5] (average)


					L0423Z5LDW

CYTOCHROME P450 2C8

METABOLIC ENZYME -> SUBSTRATE


					4T36H88UA7

APALUTAMIDE

CUMULATIVE EXCRETION

Qualification:

URINE

Amount:

MOLE PERCENT OF AMOUNT ADMINISTERED 65 % (average)


					6D53G0FD0Z

PLASMA PROTEIN FRACTION (HUMAN)

BINDER->LIGAND

Interaction Type:

BINDING

Amount:

MOLE PERCENT 96 % (average)

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Related Record

Type

Details


					Y58Z86OCE2

4-(7-(6-CYANO-5-(TRIFLUOROMETHYL)PYRIDIN-3-YL)-8-OXO-6-THIOXO-5,7-DIAZASPIRO(3.4)OCTAN-5-YL)-2-FLUOROBENZOIC ACID

METABOLITE -> PARENT

Qualification:

PLASMA


					MV57FQG9XK

5-(8-(3-FLUORO-4-(METHYLCARBAMOYL)PHENYL)-5-OXO-7-THIOXO-6,8-DIAZASPIRO(3.4)OCTAN-6-YL)-3-(TRIFLUOROMETHYL)PYRIDINE-2-CARBOXAMIDE

METABOLITE -> PARENT

Qualification:

FECAL; URINE


					T3HF86RC8H

(2S,3S,4S,5R,6S)-6-(1-(4-CARBAMOYL-3-FLUORO-ANILINO)CYCLOBUTANECARBONYL)OXY-3,4,5-TRIHYDROXY-TETRAHYDROPYRAN-2-CARBOXYLIC ACID

METABOLITE -> PARENT

Qualification:

URINE


					WP3N26Z5H4

4-THIAZOLECARBOXYLIC ACID, 2-(5-(5-(3-FLUORO-4-((METHYLAMINO)CARBONYL)PHENYL)-8-OXO-6-THIOXO-5,7-DIAZASPIRO(3.4)OCT-7-YL)-3-(TRIFLUOROMETHYL)-2-PYRIDINYL)-4,5-DIHYDRO-

METABOLITE -> PARENT

Comments:

After oral administration of 240 mg of apalutamide in 0-1680 hours

Qualification:

URINE

Amount:

0.5 % (average)
of the administered dose


					T8AA7U442W

5-(8-(4-CARBAMOYL-3-FLUORO-PHENYL)-5-OXO-7-THIOXO-6,8-DIAZASPIRO(3.4)OCTAN-6-YL)-3-(TRIFLUOROMETHYL)PYRIDINE-2-CARBOXAMIDE

METABOLITE -> PARENT

Interaction Type:

TRACE

Qualification:

FECAL

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Related Record

Type

Details


					4T36H88UA7

APALUTAMIDE

ACTIVE MOIETY

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Name	Property Type	Amount	Parameters
Volume of Distribution	PHARMACOKINETIC	276 LITERS (average)	ROUTE OF ADMINISTRATION PHARMACOKINETIC ORAL DOSE PHARMACOKINETIC 240 mg (average)

Biological Half-life	PHARMACOKINETIC	100.8 hours (average)	ROUTE OF ADMINISTRATION PHARMACOKINETIC ORAL DOSE PHARMACOKINETIC 240 mg (average)

Cmax	PHARMACOKINETIC	6 microgram/mL (average)	ROUTE OF ADMINISTRATION PHARMACOKINETIC ORAL DOSE PHARMACOKINETIC 240 mg (average)

Tmax	PHARMACOKINETIC	2 hours [1 to 5] (average)	ROUTE OF ADMINISTRATION PHARMACOKINETIC ORAL DOSE PHARMACOKINETIC 240 mg (average)

Tmax	PHARMACOKINETIC	4 hours (average) NO EFFECT ON AUC OR Cmax	DOSE PHARMACOKINETIC 240 mg (average) WITH FOOD ROUTE OF ADMINISTRATION PHARMACOKINETIC ORAL

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