SEVITERONEL

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C18H17F4N3O3
Molecular Weight	399.3395
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC(C)[C@@](O)(C1=CN=NN1)C2=CC=C3C=C(OC(F)F)C(OC(F)F)=CC3=C2

InChI

InChIKey=ZBRAJOQFSNYJMF-SFHVURJKSA-N

InChI=1S/C18H17F4N3O3/c1-9(2)18(26,15-8-23-25-24-15)12-4-3-10-6-13(27-16(19)20)14(28-17(21)22)7-11(10)5-12/h3-9,16-17,26H,1-2H3,(H,23,24,25)/t18-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C18H17F4N3O3
Molecular Weight	399.3395
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Seviteronel (VT-464) is a 17,20-lyase selective inhibitor of CYP17A1, which plays key roles in adrenal and intratumoral de novo biosynthesis of androgens. The inhibition of 17,20-lyase activity by seviteronel (VT-464) is enough to reduce androgen levels, and its preserving of 17alpha-hydroxylase activity largely avoids interference with the production of other steroidal hormones. Seviteronel (VT-464) also has shown AR-antagonist activity independent of CYP17 enzyme inhibition. It is currently in phase 2 clinical trials as a therapeutic for castration-resistant prostate cancer patients.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Androgen Receptor 167	Antagonist 2,778		5.0 µM [IC50]
Cytochrome P450 17A1 8	Inhibitor 8,297		69.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Breast cancer 434	Primary		Phase II 1,132	SEVITERONEL
Castrate-resistant prostate cancer 20	Primary		Phase II 1,132	SEVITERONEL

C_max

Value	Dose	Analyte	Population
4506 ng/mL	450 mg single, oral	SEVITERONEL plasma	Homo sapiens
7822 ng/mL	750 mg single, oral	SEVITERONEL plasma	Homo sapiens
5600 ng/mL	900 mg single, oral	SEVITERONEL plasma	Homo sapiens
5.65 mg/L	750 mg 1 times / day steady-state, oral	SEVITERONEL plasma	Homo sapiens
5.11 mg/L	750 mg single, oral	SEVITERONEL plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
31124 ng × h/mL	450 mg single, oral	SEVITERONEL plasma	Homo sapiens
84558 ng × h/mL	750 mg single, oral	SEVITERONEL plasma	Homo sapiens
79824 ng × h/mL	900 mg single, oral	SEVITERONEL plasma	Homo sapiens
63.5 mg × h/L	750 mg 1 times / day steady-state, oral	SEVITERONEL plasma	Homo sapiens
44.2 mg × h/L	750 mg single, oral	SEVITERONEL plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
6.4 h	450 mg single, oral	SEVITERONEL plasma	Homo sapiens
6.8 h	750 mg single, oral	SEVITERONEL plasma	Homo sapiens
18.3 h	750 mg 1 times / day steady-state, oral	SEVITERONEL plasma	Homo sapiens
10.5 h	750 mg single, oral	SEVITERONEL plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
900 mg 1 times / day multiple, oral Highest studied dose	unhealthy, ADULT	DLT: Muscular weakness...
450 mg 1 times / day multiple, oral RP2D	unhealthy, ADULT
600 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT	DLT: Mental status changes, Delirium...
750 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT	DLT: Confusional state, Paranoia...

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AEs

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AE	Significance	Dose	Population
Muscular weakness	grade 3, 100% DLT	900 mg 1 times / day multiple, oral Highest studied dose	unhealthy, ADULT
Delirium	grade 3, 16.7% DLT	600 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT
Mental status changes	grade 3, 16.7% DLT	600 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT
Confusional state	grade 3, 16.7% DLT	750 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT
Paranoia	grade 3, 16.7% DLT	750 mg 1 times / day multiple, oral Studied dose	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1,587	inhibitor 1,767	inhibitor 1,852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	P-gp 1,537

Drug as perpetrator

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Target	Modality	Activity
CYP2C9 1,819	inhibitor 3,277	yes [IC50 1.0684 uM]
CYP2D6 1,891	inhibitor 3,277	yes [IC50 1.6933 uM]
CYP3A4 1,925	inhibitor 3,277	yes [IC50 15.0916 uM]

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Drug as victim

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Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1,537	substrate 3,367	no

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PubMed

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Title	Date	PubMed
Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors.	2014 Jun 1	24775307
Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer.	2014 May-Jun	24759590
Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer.	2015 Jan	25351916

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Patents

Sample Use Guides

In Vivo Use Guide

In PhaseI/II clinical trial VT-464 was administered orally to patients with castration-resistant prostate cancer at the doses of 150 mg in tablet and 50 mg in capsule forms.

Route of Administration: Oral

In Vitro Use Guide

In prostate cancer cell line C4-2, both abiraterone and VT-464 significantly decreased AR transactivation. At the 1 uM and 5 uM doses, this was significantly greater with VT-464 compared with abiraterone (P < 0.01).

Substance Class	Chemical
Record UNII	8S5OIN36X4
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

SEVITERONEL

Official Name

English

VT-464

Code

English

1H-1,2,3-TRIAZOLE-5-METHANOL, .ALPHA.-(6,7-BIS(DIFLUOROMETHOXY)-2-NAPHTHALENYL)-.ALPHA.-(1-METHYLETHYL)-, (.ALPHA.S)-

Systematic Name

English

seviteronel [INN]

Common Name

English

(1S)-1-(6,7-BIS(DIFLUOROMETHOXY)NAPHTHALEN-2-YL)-2-METHYL-1-(1H-1,2,3-TRIAZOLE-4-YL)PROPAN-1-OL

Systematic Name

English

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Classification Tree

Code System

Code

Anti-Androgen

NCI_THESAURUS

C147923

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Code System

Code

Type

Description

WIKIPEDIA

VT-464

PRIMARY

SMS_ID

100000175299

PRIMARY

FDA UNII

8S5OIN36X4

PRIMARY

CAS

1610537-15-9

PRIMARY

NCI_THESAURUS

C113652

PRIMARY

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Related Record

Type

Details


					6X5FNK3DCM

CYTOCHROME P450 17A1

TARGET -> INHIBITOR

Amount:

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Related Record

Type

Details


					8S5OIN36X4

SEVITERONEL

ACTIVE MOIETY

Amount:

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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator