Linzagolix

Identification

Summary

Linzagolix is a selective gonadotropin-releasing hormone (GnRH) receptor antagonist used for the symptomatic treatment of uterine fibroids.

Generic Name

Linzagolix

DrugBank Accession Number

DB17083

Background

Linzagolix is a non-peptide, selective antagonist of the gonadotropin-releasing hormone (GnRH) receptor. It has been studied for the treatment of estrogen-dependent conditions such as uterine fibroids and endometriosis.^1,2 It is similar to other GnRH receptor antagonists like cetrorelix, relugolix, and elagolix.

Uterine fibroids occur in >70% of women of reproductive age, and when symptomatic are associated with heavy menstrual bleeding, anemia, abdominal pain and pressure, bloating, increased urinary frequency, and reproductive dysfunction.⁵ As these fibroids are essentially estrogen-dependent phenomena, hormone therapies which suppress estrogen activity - including GnRH receptor antagonists like linzagolix - are thought to be beneficial by preventing intramyometrial growths in the endometrial glands.⁶

Linzagolix was approved for use in the European Union in June 2022 for the management of symptoms caused by uterine fibroids.⁷

Type

Small Molecule

Groups

Approved

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Linzagolix (DB17083)

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Weight

Average: 508.42
Monoisotopic: 508.055206494

Chemical Formula

C₂₂H₁₅F₃N₂O₇S

Synonyms

• 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy)-2-fluoro-4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno(3,4-d)pyrimidine-5-carboxylic acid
• Linzagolix
• Thieno(3,4-d)pyrimidine-5-carboxylic acid, 3-(5-((2,3-difluoro-6-methoxyphenyl)methoxy)-2-fluoro-4-methoxyphenyl)-1,2,3,4-tetrahydro-2,4-dioxo-

External IDs

• OBE-2109

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Pharmacology

Indication

Linzagolix is indicated for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.⁷

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Symptomatic treatment of	Moderate uterine fibroids		••••••••••••	•••••	•••••••••••• •••••••••	••••••• •••• ••••••
Symptomatic treatment of	Severe uterine fibroids		••••••••••••	•••••	•••••••••••• •••••••••	••••••• •••• ••••••

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Pharmacodynamics

The administration of linzagolix results in a dose-dependent suppression of luteinizing hormone and follicle-stimulating hormone, and a subsequent decrease in circulating estradiol concentrations.⁷ The median serum estradiol levels across all studied patients was in the range of 20 to 60 pg/mL, and progesterone levels were maintained ≤3.1 ng/mL in 83% of women receiving the 200mg dose of linzagolix and 68% of women receiving the 100mg dose.⁷

Linzagolix should be avoided in patients with severe hepatic impairment (Child-Pugh C) and in patients with moderate, severe, or end-stage renal disease (eGFR ≤59 mL/min).⁷ Some patients experienced a reduction in bone mineral density, varying from 3 to 8% - patients with an increased risk of fracture or osteoporosis should be monitored closely and should receive regular bone density scans to assess any on-going loss.⁷

Mechanism of action

Linzagolix is a selective antagonist of the gonadotropin-releasing hormone (GnRH) receptor. It binds competitively to GnRH receptors in the pituitary gland, thereby inhibiting endogenous signaling and, in turn, the hypothalamic-pituitary-gonadal axis.⁷ More specifically, this inhibition of GnRH signaling results in the suppression of both luteinizing hormone and follicle-stimulating hormone signaling, the latter of which is responsible for stimulating the production of estrogen in the ovaries.⁶ Linzagolix, therefore, indirectly suppresses estrogen production and signaling, making it useful in the management of estrogen-dependent conditions like uterine fibroids.

Target	Actions	Organism
AGonadotropin-releasing hormone receptor	antagonist	Humans

Absorption

Linzagolix is quickly absorbed following oral administration, with C_max occurring approximately 2 hours following administration.⁷

Volume of distribution

After seven days of oral administration of linzagolix 100mg or 200mg, the volume of distribution was 11.067 L and 11.178 L, respectively.⁷

Protein binding

Linzagolix is highly protein-bound (>99%) in plasma, primarily to albumin.⁷

Metabolism

Up to seven metabolites of linzagolix have been quantified in patient plasma, urine, and feces, although plasma metabolites represent less than 10% of the total linzagolix-related exposure.⁷ Two primary demethylated metabolites - KP017 and KP046 - have been identified, with CYP2C9 primarily responsible for the formation of KP017 and CYP2C8, CYP2C9, and CYP3A4 are primarily responsible for the formation of KP046.⁸ Unchanged parent drug is the predominant circulating component in human plasma and in the urine, and one of the major components in the feces.⁷

Route of elimination

Linzagolix is primarily excreted in the urine, with approximately one-third eliminated via the feces.⁷

Half-life

The half-life of linzagolix following multiple doses is approximately 15 hours.⁷

Clearance

The geometric mean apparent clearance following multiple oral doses of linzagolix 100mg or 200mg was 0.522 L/h and 0.499 L/h, respectively.⁷

Adverse Effects

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Toxicity

No data regarding overdosage with linzagolix are available. In the event of a suspected overdose, patients should be monitored closely. Institute symptomatic and supportive measures as clinically indicated.

Pathways

Not Available

Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">

Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Almotriptan	The serum concentration of Almotriptan can be increased when it is combined with Linzagolix.
Aminophenazone	The serum concentration of Aminophenazone can be increased when it is combined with Linzagolix.
Amiodarone	The serum concentration of Amiodarone can be increased when it is combined with Linzagolix.
Amitriptyline	The serum concentration of Amitriptyline can be increased when it is combined with Linzagolix.
Amodiaquine	The serum concentration of Amodiaquine can be increased when it is combined with Linzagolix.

Food Interactions

• Take with or without food. The co-administration of linzagolix with food does not effect its pharmacokinetics to a clinically significant extent.

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Linzagolix choline	VHS6SC660Q	1321816-57-2	IAIVRTFCYOGNBW-UHFFFAOYSA-M

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Yselty	Tablet, film coated	100 mg	Oral	Theramex Ireland Limited	2022-07-15	Not applicable
Yselty	Tablet, film coated	100 mg	Oral	Theramex Ireland Limited	2023-05-04	Not applicable
Yselty	Tablet, film coated	200 mg	Oral	Theramex Ireland Limited	2023-05-04	Not applicable
Yselty	Tablet, film coated	200 mg	Oral	Theramex Ireland Limited	2022-07-15	Not applicable

Categories

ATC Codes

H01CC04 — Linzagolix

• H01CC — Anti-gonadotropin-releasing hormones
• H01C — HYPOTHALAMIC HORMONES
• H01 — PITUITARY AND HYPOTHALAMIC HORMONES AND ANALOGUES
• H — SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS

Drug Categories

• Anti-Gonadotropin-Releasing Hormones
• BCRP/ABCG2 Substrates
• Cytochrome P-450 CYP2C8 Inhibitors
• Cytochrome P-450 CYP2C8 Inhibitors (strength unknown)
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Gonadotropin Releasing Hormone Receptor Antagonists
• Hypothalamic Hormones
• OAT1/SLC22A6 inhibitors
• OAT3/SLC22A8 Inhibitors
• OAT3/SLC22A8 Substrates
• OATP1B1/SLCO1B1 Inhibitors
• OATP1B1/SLCO1B1 Substrates
• OATP1B3 inhibitors
• OATP1B3 substrates
• Pituitary and Hypothalamic Hormones and Analogues
• Systemic Hormonal Preparations, Excl. Sex Hormones and Insulins

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

7CDW97HUEX

CAS number

935283-04-8

InChI Key

BMAAMIIYNNPHAB-UHFFFAOYSA-N

InChI

InChI=1S/C22H15F3N2O7S/c1-32-14-4-3-10(23)18(25)9(14)7-34-16-6-13(11(24)5-15(16)33-2)27-20(28)17-12(26-22(27)31)8-35-19(17)21(29)30/h3-6,8H,7H2,1-2H3,(H,26,31)(H,29,30)

IUPAC Name

3-{5-[(2,3-difluoro-6-methoxyphenyl)methoxy]-2-fluoro-4-methoxyphenyl}-2,4-dioxo-1H,2H,3H,4H-thieno[3,4-d]pyrimidine-5-carboxylic acid

SMILES

COC1=C(COC2=C(OC)C=C(F)C(=C2)N2C(=O)NC3=CSC(C(O)=O)=C3C2=O)C(F)=C(F)C=C1

References

Synthesis Reference

Ohno, K., Miyagi, T., Ozawa, T., & Fushimi, N. (2007, April 26). Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof . WO2007046392A1.

General References

1. Donnez J, Taylor HS, Taylor RN, Akin MD, Tatarchuk TF, Wilk K, Gotteland JP, Lecomte V, Bestel E: Treatment of endometriosis-associated pain with linzagolix, an oral gonadotropin-releasing hormone-antagonist: a randomized clinical trial. Fertil Steril. 2020 Jul;114(1):44-55. doi: 10.1016/j.fertnstert.2020.02.114. Epub 2020 Jun 4. [Article]
2. Dababou S, Garzon S, Lagana AS, Ferrero S, Evangelisti G, Noventa M, D'Alterio MN, Palomba S, Uccella S, Franchi M, Barra F: Linzagolix: a new GnRH-antagonist under investigation for the treatment of endometriosis and uterine myomas. Expert Opin Investig Drugs. 2021 Sep;30(9):903-911. doi: 10.1080/13543784.2021.1957830. Epub 2021 Aug 4. [Article]
3. Donnez J, Donnez O, Tourniaire J, Brethous M, Bestel E, Garner E, Charpentier S, Humberstone A, Loumaye E: Uterine Adenomyosis Treated by Linzagolix, an Oral Gonadotropin-Releasing Hormone Receptor Antagonist: A Pilot Study with a New 'Hit Hard First and then Maintain' Regimen of Administration. J Clin Med. 2021 Dec 10;10(24). pii: jcm10245794. doi: 10.3390/jcm10245794. [Article]
4. Tezuka M, Tamai Y, Kuramochi Y, Kobayashi K, Fushimi N, Kiguchi S: Pharmacological characterization of linzagolix, a novel, orally active, non-peptide antagonist of gonadotropin-releasing hormone receptors. Clin Exp Pharmacol Physiol. 2022 Oct;49(10):1082-1093. doi: 10.1111/1440-1681.13688. Epub 2022 Jul 12. [Article]
5. Keam SJ: Linzagolix: First Approval. Drugs. 2022 Aug;82(12):1317-1325. doi: 10.1007/s40265-022-01753-9. [Article]
6. Donnez J, Stratopoulou CA, Dolmans MM: Uterine Adenomyosis: From Disease Pathogenesis to a New Medical Approach Using GnRH Antagonists. Int J Environ Res Public Health. 2021 Sep 22;18(19). pii: ijerph18199941. doi: 10.3390/ijerph18199941. [Article]
7. EMA Summary of Product Characteristics: Yselty (linzagolix choline) film-coated tablets for oral administration [Link]
8. CHMP Public Assessment Report: Linzagolix choline [Link]

External Links

ChemSpider

17590169

BindingDB

160329

RxNav

2621019

ChEMBL

CHEMBL3668014

ZINC

ZINC000043152963

Wikipedia

Linzagolix

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Endometriosis	1
3	Completed	Treatment	Endometriosis	1
3	Completed	Treatment	Heavy Menstrual Bleeding / Uterine Fibroids (Leiomyomas)	2
3	Terminated	Treatment	Endometriosis	2
2	Completed	Treatment	Endometriosis	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Powder		1 kg/1kg
Tablet, film coated	Oral	100 mg
Tablet, film coated	Oral	200 mg

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Slightly soluble	https://www.ema.europa.eu/en/documents/assessment-report/yselty-epar-public-assessment-report_en.pdf

Predicted Properties

Property	Value	Source
Water Solubility	0.00198 mg/mL	ALOGPS
logP	3.2	ALOGPS
logP	3.88	Chemaxon
logS	-5.4	ALOGPS
pKa (Strongest Acidic)	3.15	Chemaxon
pKa (Strongest Basic)	-3.5	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	7	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	114.4 Å2	Chemaxon
Rotatable Bond Count	6	Chemaxon
Refractivity	117.25 m3·mol-1	Chemaxon
Polarizability	45.39 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Not Available

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Gonadotropin-releasing hormone receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Peptide binding

Specific Function

Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone...

Gene Name

GNRHR

Uniprot ID

P30968

Uniprot Name

Gonadotropin-releasing hormone receptor

Molecular Weight

37730.355 Da

References

1. Tezuka M, Tamai Y, Kuramochi Y, Kobayashi K, Fushimi N, Kiguchi S: Pharmacological characterization of linzagolix, a novel, orally active, non-peptide antagonist of gonadotropin-releasing hormone receptors. Clin Exp Pharmacol Physiol. 2022 Oct;49(10):1082-1093. doi: 10.1111/1440-1681.13688. Epub 2022 Jul 12. [Article]
2. EMA Summary of Product Characteristics: Yselty (linzagolix choline) film-coated tablets for oral administration [Link]

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Drug created at October 26, 2022 14:34 / Updated at December 13, 2022 10:46