An official website of the United States government

Fezolinetant

PubChem CID
117604931
Structure
Fezolinetant_small.png
Fezolinetant_3D_Structure.png
Molecular Formula
Synonyms
  • Fezolinetant
  • 1629229-37-3
  • ESN364
  • VEOZAH
  • ESN-364
Molecular Weight
358.4 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2016-02-23
  • Modify:
    2024-12-28
Description
Fezolinetant is a triazolopyrazine that is 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine substituted by 3-methyl-1,2,4-thiadiazol-5-yl, 4-fluorobenzoyl and methyl groups at positions 3, 7, and 8R, respectively. It is a prescription medicine used to reduce moderate to severe vasomotor symptoms due to menopause. It has a role as a neurokinin-3 receptor antagonist. It is a member of monofluorobenzenes, a triazolopyrazine, a member of thiadiazoles, a member of benzamides and a tertiary carboxamide.
Vasomotor symptoms (VMS), more colloquially known as hot flashes or night sweats, are some of the most common symptoms in menopause. With a median duration of 7.4 years, vasomotor symptoms are also the most common reasons why women seek treatments for menopausal issues. Although mostly considered a nuisance, vasomotor symptoms can significantly affect quality of life, as women with 7 or more moderate to severe VMS daily have reported a decline in sleep quality, concentration, sexual activity, energy, and concentration. Although the pathophysiology of VMS is not fully understood, unpredictable fluctuation in estrogen levels is thought to be the main cause of VMS, as estrogen therapy has been one of the most effective treatments for VMS by relieving symptoms in as many as 95% of menopausal women. Women undergoing abrupt menopause due to oophorectomy also experienced more severe symptoms than those going through a gradual transition. Additionally, thermoregulatory dysfunction has been proposed as one of the three possible mechanisms for VMS in menopause. Estrogen is a potent neuromodulator, particularly in the hypothalamus, and has been shown to be involved as a negative regulator in generating Gonadotropin-releasing hormone (GnRH) pulse through the kisspeptin, neurokinin B, and dynorphin (KNDy) neurons. NK3, one of the receptors expressed in KNDy neurons, is activated by neurokinin B and can thus induce the release of GnRH. Lower estrogen levels during menopause will decrease the estrogen-mediated feedback loop and increase neurokinin B signalling, increasing the activity of KNDy neurons and therefore the activity of the temperature control center. By antagonizing NK3 receptors, neuronal signalling can be dampened to reduce VMS. Although hormone therapy is available for menopausal women, safety and tolerability concerns, such as an increased risk of stroke and venous thromboembolism or hormone-dependent cancer like breast cancer, can prevent some women from receiving this treatment. Fezolinetant, an NK3 receptor antagonist, was developed in response to this issue as well as more understanding of the role of NK3R in the hypothalamic-pituitary-gonadal (HPG) axis. Although previous NK3 receptor antagonists exist, such as osanetant and talnetant, only fezolinetant showed tangible effects on the HPC axis, potentially due to its favorable pharmacokinetics profile to cross the blood-brain barrier. Fezolinetant was approved by the FDA in May 2023 under the brand name Veozah. It was subsequently approved by the EMA in December 2023 for the same indication.
Fezolinetant is a Neurokinin 3 Receptor Antagonist. The mechanism of action of fezolinetant is as a Neurokinin 3 Receptor Antagonist.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Fezolinetant.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(4-fluorophenyl)-[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]methanone
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 InChI

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
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

PPSNFPASKFYPMN-SECBINFHSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

C[C@@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C
Computed by OEChem 2.3.0 (PubChem release 2024.11.20)

2.2 Molecular Formula

C16H15FN6OS
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 Metabolomics Workbench ID

2.3.9 NCI Thesaurus Code

2.3.10 PharmGKB ID

2.3.11 RXCUI

2.3.12 Wikidata

2.3.13 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • ESN364
  • fezolinetant
  • veozah

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
358.4 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3-AA
Property Value
1.6
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
358.10120846 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
358.10120846 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
105Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
25
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
505
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Solubility

0.29mg/mL
L46422

3.3 Chemical Classes

3.3.1 Drugs

3.3.1.1 Human Drugs
Human drug -> Active ingredient (FEZOLINETANT)
Human drug -> Prescription

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.

6.2 LiverTox Summary

Fezolinetant is an orally available neurokinin 3 receptor antagonist that is used to treat women with vasomotor symptoms (such as hot flashes) due to menopause. Fezolinetant is associated with a low rate of serum aminotransferase elevations during therapy and has been linked to rare instances of clinically apparent liver injury with jaundice.

6.3 Drug Classes

Obstetrical and Gynecological Agents

6.4 FDA Approved Drugs

6.5 FDA Orange Book

6.6 FDA National Drug Code Directory

6.7 Drug Labels

Drug and label
Active ingredient and drug

6.8 Clinical Trials

6.8.1 ClinicalTrials.gov

6.8.2 EU Clinical Trials Register

6.8.3 NIPH Clinical Trials Search of Japan

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

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 for NK1 or NK2 receptors. Treatment with fezolinetant did not show any clear trends in sex hormones measured (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women. A transient decrease of luteinizing hormone (LH) levels was observed at peak concentrations of fezolinetant. At a dose 20 times the maximum approved recommended dose, fezolinetant does not prolong the QT interval to any clinically relevant extent. In a phase 2a clinical trial, fezolinetant 90 mg BID significantly reduce the frequency and severity of vasomotor symptoms in postmenopausal women by more than 50%. The improvement was observed as early as in the first week of treatment and was maintained throughout the 12 weeks of treatment.

7.2 FDA Pharmacological Classification

1 of 2
FDA UNII
83VNE45KXX
Active Moiety
FEZOLINETANT
Pharmacological Classes
Established Pharmacologic Class [EPC] - Neurokinin 3 Receptor Antagonist
Pharmacological Classes
Mechanisms of Action [MoA] - Neurokinin 3 Receptor Antagonists
FDA Pharmacology Summary
Fezolinetant is a Neurokinin 3 Receptor Antagonist. The mechanism of action of fezolinetant is as a Neurokinin 3 Receptor Antagonist.
2 of 2
Non-Proprietary Name
FEZOLINETANT
Pharmacological Classes
Neurokinin 3 Receptor Antagonists [MoA]; Neurokinin 3 Receptor Antagonist [EPC]

7.3 ATC Code

G - Genito urinary system and sex hormones

G02 - Other gynecologicals

G02C - Other gynecologicals

G02CX - Other gynecologicals

G02CX06 - Fezolinetant

7.4 Absorption, Distribution and Excretion

Absorption
In healthy women, fezolinetant Cmax and AUC increased proportionally over a dosage range from 20 to 60 mg once daily (0.44 to 1.33 times the approved recommended dosage). Steady-state plasma concentrations of fezolinetant were reached after two once-daily doses, with minimal fezolinetant accumulation. The median (range) time to reach fezolinetant Cmax is 1.5 (1 to 4) hours in healthy women.
Route of Elimination
Following oral administration of fezolinetant, 76.9% of the dose was excreted in urine (1.1% unchanged) and 14.7% in feces (0.1% unchanged).
Volume of Distribution
The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 L.
Clearance
The apparent clearance at steady state of fezolinetant is 10.8 L/h.

7.5 Metabolism / Metabolites

Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19. A major metabolite of fezolinetant, ES259564, was identified in plasma. ES259564 is approximately 20-fold less potent than the parent. The metabolite-to-parent ratio ranges from 0.7 to 1.8.

7.6 Biological Half-Life

The effective half-life (t1/2) of fezolinetant is 9.6 hours in women with vasomotor symptoms.

7.7 Mechanism of Action

Fezolinetant 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.

8 Use and Manufacturing

8.1 Uses

8.1.1 Use Classification

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9 Safety and Hazards

9.1 Hazards Identification

9.1.1 GHS Classification

GHS Hazard Statements

Not Classified

Reported as not meeting GHS hazard criteria by 1 of 1 companies. For more detailed information, please visit ECHA C&L website.

9.1.2 Hazard Classes and Categories

Not Classified

10 Toxicity

10.1 Toxicological Information

10.1.1 Hepatotoxicity

In preregistration clinical trials, serum ALT or AST elevations above 3 times the upper limit of normal (ULN) occurred in 2.3% of patients taking fezolinetant vs 0.9% of placebo recipients. The elevations were largely asymptomatic and transient, resolving promptly after stopping therapy and sometimes despite drug continuation. Nevertheless, the elevations appeared to be related to therapy and arose most frequently during the first few months of treatment. More striking elevations arose in early phase trials using higher doses of fezolinetant. Bilirubin elevations were rare and there were no instances of clinically apparent liver injury with jaundice in preregistration clinical studies even with high doses. However, within a year of its approval, a case of mixed-cholestatic hepatitis with symptoms and jaundice occurred in a patient taking fezolinetant. The episode arose within 54 days of starting fezolinetant and resolved once the drug was stopped. Because of this case, the warning about drug induced liver injury was strengthened, and more explicit recommendations were made regarding prescreening and monitoring patients in the product label of fezolinetant.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

10.1.2 Protein Binding

The plasma protein binding of fezolinetant is 51%. The blood-to-plasma ratio is 0.9.

11 Associated Disorders and Diseases

12 Literature

12.1 Consolidated References

12.2 NLM Curated PubMed Citations

12.3 Springer Nature References

12.4 Chemical Co-Occurrences in Literature

12.5 Chemical-Gene Co-Occurrences in Literature

12.6 Chemical-Disease Co-Occurrences in Literature

13 Patents

13.1 Depositor-Supplied Patent Identifiers

13.2 WIPO PATENTSCOPE

13.3 FDA Orange Book Patents

13.4 Chemical Co-Occurrences in Patents

13.5 Chemical-Disease Co-Occurrences in Patents

13.6 Chemical-Gene Co-Occurrences in Patents

14 Interactions and Pathways

14.1 Chemical-Target Interactions

14.2 Drug-Drug Interactions

15 Biological Test Results

15.1 BioAssay Results

16 Classification

16.1 MeSH Tree

16.2 NCI Thesaurus Tree

16.3 ChEBI Ontology

16.4 WHO ATC Classification System

16.5 ChemIDplus

16.6 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

16.7 ChEMBL Target Tree

16.8 UN GHS Classification

16.9 EPA DSSTox Classification

16.10 FDA Drug Type and Pharmacologic Classification

16.11 PFAS and Fluorinated Organic Compounds in PubChem

16.12 MolGenie Organic Chemistry Ontology

17 Information Sources

  1. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
    [(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
    https://commonchemistry.cas.org/detail?cas_rn=1629229-37-3
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    (R)-(4-fluorophenyl)(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
    https://echa.europa.eu/substance-information/-/substanceinfo/100.306.917
    (R)-(4-fluorophenyl)(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 (EC: 855-900-3)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/302165
  6. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. ChEBI
  8. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  9. LiverTox
  10. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  11. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  12. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  13. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  14. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  15. Therapeutic Target Database (TTD)
  16. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  17. DailyMed
  18. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  19. EU Clinical Trials Register
  20. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  21. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  22. Metabolomics Workbench
  23. NIPH Clinical Trials Search of Japan
  24. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  25. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  26. Springer Nature
  27. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  28. Wikidata
  29. Wikipedia
  30. PubChem
  31. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  32. GHS Classification (UNECE)
  33. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  34. PATENTSCOPE (WIPO)
CONTENTS