FEZOLINETANT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C16H15FN6OS
Molecular Weight	358.393
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@H]1N(CCN2C1=NN=C2C3=NC(C)=NS3)C(=O)C4=CC=C(F)C=C4

InChI

InChIKey=PPSNFPASKFYPMN-SECBINFHSA-N

InChI=1S/C16H15FN6OS/c1-9-13-19-20-14(15-18-10(2)21-25-15)23(13)8-7-22(9)16(24)11-3-5-12(17)6-4-11/h3-6,9H,7-8H2,1-2H3/t9-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://pubmed.ncbi.nlm.nih.gov/37462862|https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf

Fezolinetant (VEOZAH™) is an oral, small molecule, neurokinin 3 receptor (NK3R) antagonist, which is being developed by Astellas Pharma Inc. for the treatment of moderate to severe vasomotor symptoms (VMS) or hot flashes due to menopause. Inhibiting NK3R-mediated signaling in the central nervous system is a non-hormonal strategy to modulate the activity of neurons that are associated with thermoregulation, thereby reducing the frequency and severity of VMS. VEOZAH is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center. Fezolinetant has a high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than the binding affinity to NK1 or NK2 receptors. Fezolinetant received its first approval in the USA in May 2023 for the treatment of moderate to severe VMS due to menopause.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Neurokinin 3 receptor 8 Target ID: CHEMBL4429 Gene ID: 6870.0 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26191358	Antagonist 2849		7.6 null [pKi]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Vasomotor symptoms due to menopause 5 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf	Primary		Approved 8583	VEOZAH Approved Use VEOZAH is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. Launch Date 2023

C_max

Value	Dose	Analyte	Population
77.5 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	12 mg single, oral dose: 12 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
307 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	46 mg single, oral dose: 46 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
545 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
1110 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
104 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
319 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
877 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
185 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED
423 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED
1720 ng/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED

AUC

Value	Dose	Analyte	Population
418 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	12 mg single, oral dose: 12 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
1620 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	46 mg single, oral dose: 46 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
3280 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
7190 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
539 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
2000 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
5940 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
1130 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED
2880 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED
5940 ng × h/mL EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED

T_1/2

Value	Dose	Analyte	Population
9.6 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN
3.69 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	12 mg single, oral dose: 12 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
3.35 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	46 mg single, oral dose: 46 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
4.13 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	90 mg single, oral dose: 90 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
4.19 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg single, oral dose: 180 mg route of administration: Oral experiment type: SINGLE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
2.84 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
3.95 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
4.2 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
4.27 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	20 mg 1 times / day steady-state, oral dose: 20 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED
4.84 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED
6.34 h EXPERIMENT https://academic.oup.com/jcem/article/101/2/417/2810542	180 mg 1 times / day steady-state, oral dose: 180 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: FED

F_unbound

Value	Dose	Co-administered	Analyte	Population
49% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf	60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		FEZOLINETANT plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 inhibitor 2252	inhibitor 2438 substrate 1193	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 2057 CYP2C8 1057 CYP1A2 2153 CYP2B6 926 P-gp 1741 OAT1 725 OATP1B1 1079 BCRP 910 OAT3 747 OATP1B3 961 OCT2 779 MATE1 415 MATE2-K 77	P-gp 2052 OATP1B1 503 BCRP 697 OATP1B3 435 CYP2C19 1119 CYP1A2 1197	CYP1A2 832 CYP2B6 669

Drug as perpetrator

Target	Modality	Activity
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12 \| 89	no
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 89.0	no
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no
MATE2-K 77	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 12.0	no

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP1A2 1197	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf#page=17 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf#page=79 Page: 19.0	major	yes (co-administration study) Comment: concomitant use of fluvoxamine (a strong CYP1A2 inhibitor) resulted in a 9.4- fold increase in fezolinetant AUCinf and 1.8-fold increase in Cmax. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000PharmR.pdf \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf#page=17 \| https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf#page=79 Page: 19.0
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 89.0	minor
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 89.0	minor
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 11.0	yes
OATP1B1 503	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 11.0	yes
OATP1B3 435	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 11.0	yes
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000ClinPharmR.pdf Page: 11.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000PharmR.pdf Page: 38 \| 60

PubMed

Title	Date	PubMed
The NK3 Receptor Antagonist ESN364 Suppresses Sex Hormones in Men and Women.	2016-02	26653113
The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle.	2015-11	26305889
Optimization of Novel Antagonists to the Neurokinin-3 Receptor for the Treatment of Sex-Hormone Disorders (Part II).	2015-07-09	26191358

Patents

Sample Use Guides

In Vivo Use Guide

One 45 mg tablet orally once daily with or without food.

Route of Administration: Oral

In Vitro Use Guide

Fezolinetant has high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L).

Name

Type

Language

fezolinetant [INN]

Preferred Name

English

FEZOLINETANT

Official Name

English

AS-3472693-00

Code

English

(4-FLUOROPHENYL)((8R)-8-METHYL-3-(3-METHYL-1,2,4- THIADIAZOL-5-YL)-5,6-DIHYDRO-1,2,4-TRIAZOLO(4,3-A)PYRAZIN- 7(8H)-YL)METHANONE

Systematic Name

English

FEZOLINETANT [USAN]

Common Name

English

METHANONE, ((8R)-5,6-DIHYDRO-8-METHYL-3-(3-METHYL-1,2,4-THIADIAZOL-5-YL)-1,2,4-TRIAZOLO(4,3-A)PYRAZIN-7(8H)-YL)(4-FLUOROPHENYL)-

Systematic Name

English

VEOZAH

Brand Name

English

ES-256364

Code

English

A-2693

Code

English

(4-FLUOROPHENYL)((8R)-5,6-DIHYDRO-8-METHYL-3-(3-METHYL-1,2,4-THIADIAZOL-5-YL)-(1,2,4)TRIAZOLO(4,3-A)PYRAZIN-7(8H)-YL)METHANONE

Systematic Name

English

A2693

Code

English

((8R)-5,6-DIHYDRO-8-METHYL-3-(3-METHYL-1,2,4-THIADIAZOL-5-YL)-1,2,4-TRIAZOLO(4,3-A)PYRAZIN-7(8H)-YL)(4-FLUOROPHENYL)METHANONE

Systematic Name

English

AS3472693-00

Code

English

ESN-364

Code

English

Fezolinetant [WHO-DD]

Common Name

English

ESN364

Code

English

Code System Code Type Description

USAN

HI-226