SEVITERONEL

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

Structure Search

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

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

Description
Sources: https://www.ncbi.nlm.nih.gov/mesh/2008829
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/27302572

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 Target ID: CHEMBL1871 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27302572	Antagonist 2778		5.0 µM [IC50]
Cytochrome P450 17A1 8 Target ID: CHEMBL3522 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27302572	Inhibitor 8297		69.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Breast cancer 434 Sources: http://meetinglibrary.asco.org/content/170182-176	Primary		Phase II 1132	SEVITERONEL Approved Use Seviteronel is currently studied in patients with breast cancer in a Phase I-II non-randomized, open-label trial in order to evaluate its safety, tolerability, pharmacokinetics and activity.
Castrate-resistant prostate cancer 20 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26954621	Primary		Phase II 1132	SEVITERONEL Approved Use The VT-464 (Seviteronel) is currently studied in 154 men with castration-resistant prostate cancer in a Phase I-II open-label, multiple-dose trial in order to evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics.

C_max

Value	Dose	Analyte	Population
5600 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30012563	900 mg single, oral dose: 900 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
5.65 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32327394	750 mg 1 times / day steady-state, oral dose: 750 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
5.11 mg/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32327394	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
4506 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29744674	450 mg single, oral dose: 450 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
7822 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29744674	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
79824 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/30012563	900 mg single, oral dose: 900 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
63.5 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32327394	750 mg 1 times / day steady-state, oral dose: 750 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
44.2 mg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32327394	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
31124 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29744674	450 mg single, oral dose: 450 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
84558 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29744674	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
18.3 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32327394	750 mg 1 times / day steady-state, oral dose: 750 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
10.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32327394	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN
6.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29744674	450 mg single, oral dose: 450 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
6.8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/29744674	750 mg single, oral dose: 750 mg route of administration: Oral experiment type: SINGLE co-administered:	SEVITERONEL plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
900 mg 1 times / day multiple, oral Highest studied dose Dose: 900 mg, 1 times / day Route: oral Route: multiple Dose: 900 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30012563 Page: p.5227	unhealthy, ADULT n = 1 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/30012563 Page: p.5227	DLT: Muscular weakness... Dose limiting toxicities: Muscular weakness (grade 3, 100%) Sources: https://pubmed.ncbi.nlm.nih.gov/30012563 Page: p.5227
450 mg 1 times / day multiple, oral RP2D Dose: 450 mg, 1 times / day Route: oral Route: multiple Dose: 450 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: breast cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5
600 mg 1 times / day multiple, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: breast cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	DLT: Mental status changes, Delirium... Dose limiting toxicities: Mental status changes (grade 3, 16.7%) Delirium (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5
750 mg 1 times / day multiple, oral Studied dose Dose: 750 mg, 1 times / day Route: oral Route: multiple Dose: 750 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: breast cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	DLT: Confusional state, Paranoia... Dose limiting toxicities: Confusional state (grade 3, 16.7%) Paranoia (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5

AEs

AE	Significance	Dose	Population
Muscular weakness	grade 3, 100% DLT	900 mg 1 times / day multiple, oral Highest studied dose Dose: 900 mg, 1 times / day Route: oral Route: multiple Dose: 900 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30012563 Page: p.5227	unhealthy, ADULT n = 1 Health Status: unhealthy Condition: prostate cancer Age Group: ADULT Sex: M Food Status: UNKNOWN Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/30012563 Page: p.5227
Delirium	grade 3, 16.7% DLT	600 mg 1 times / day multiple, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: breast cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5
Mental status changes	grade 3, 16.7% DLT	600 mg 1 times / day multiple, oral Studied dose Dose: 600 mg, 1 times / day Route: oral Route: multiple Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: breast cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5
Confusional state	grade 3, 16.7% DLT	750 mg 1 times / day multiple, oral Studied dose Dose: 750 mg, 1 times / day Route: oral Route: multiple Dose: 750 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: breast cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5
Paranoia	grade 3, 16.7% DLT	750 mg 1 times / day multiple, oral Studied dose Dose: 750 mg, 1 times / day Route: oral Route: multiple Dose: 750 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: breast cancer Age Group: ADULT Sex: F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/29744674 Page: p.5

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	P-gp 1537

Drug as perpetrator

Target	Modality	Activity
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363681413	yes [IC50 1.0684 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363681413	yes [IC50 1.6933 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363681413	yes [IC50 15.0916 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363680966	no

PubMed

Title	Date	PubMed
Recent progress in pharmaceutical therapies for castration-resistant prostate cancer.	2013 Jul 4	23880851
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
Novel and next-generation androgen receptor-directed therapies for prostate cancer: Beyond abiraterone and enzalutamide.	2016 Aug	26162486

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 Created by `admin` on `Sat Dec 16 09:05:14 UTC 2023` Edited by `admin` on `Sat Dec 16 09:05:14 UTC 2023`
Record UNII	8S5OIN36X4
Record Status	`Validated (UNII)`
Record Version

Download

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

Seviteronel [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C147923