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

Similar Structures

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		••••••••••••	•••••	•••••••••••• •••••••••	••••••• •••• ••••••

Contraindications & Blackbox Warnings

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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

Not Available

Interactions

Drug Interactions

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.

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.

Products

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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
Yselty	Tablet, film coated	200 mg	Oral	Theramex Ireland Limited	2022-07-15	Not applicable
Yselty	Tablet, film coated	200 mg	Oral	Theramex Ireland Limited	2023-05-04	Not applicable
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

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

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]
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]
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]
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]
Keam SJ: Linzagolix: First Approval. Drugs. 2022 Aug;82(12):1317-1325. doi: 10.1007/s40265-022-01753-9. [Article]
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]
EMA Summary of Product Characteristics: Yselty (linzagolix choline) film-coated tablets for oral administration [Link]
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

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Endometriosis	2
3	Completed	Treatment	Menstrual Bleeding, Heavy / Uterine Fibroids (Leiomyomas)	2
3	Terminated	Treatment	Endometriosis	2
2	Completed	Treatment	Endometriosis	1
1	Completed	Basic Science	Healthy Volunteers (HV) / Hepatic Impairment	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

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]
EMA Summary of Product Characteristics: Yselty (linzagolix choline) film-coated tablets for oral administration [Link]

Enzymes

Details1. Cytochrome P450 2C9

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Steroid hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP2C9
Uniprot ID: P11712
Uniprot Name: Cytochrome P450 2C9
Molecular Weight: 55627.365 Da

References

CHMP Public Assessment Report: Linzagolix choline [Link]

Details2. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Vitamin d3 25-hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

CHMP Public Assessment Report: Linzagolix choline [Link]

Details3. Cytochrome P450 2C8

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: Steroid hydroxylase activity
Specific Function: Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name: CYP2C8
Uniprot ID: P10632
Uniprot Name: Cytochrome P450 2C8
Molecular Weight: 55824.275 Da

References

EMA Summary of Product Characteristics: Yselty (linzagolix choline) film-coated tablets for oral administration [Link]
CHMP Public Assessment Report: Linzagolix choline [Link]

Carriers

Details1. Serum albumin

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Binder

General Function: Toxic substance binding
Specific Function: Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name: ALB
Uniprot ID: P02768
Uniprot Name: Serum albumin
Molecular Weight: 69365.94 Da

References

EMA Summary of Product Characteristics: Yselty (linzagolix choline) film-coated tablets for oral administration [Link]

Transporters

Details1. Solute carrier organic anion transporter family member 1B1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

References

CHMP Public Assessment Report: Linzagolix choline [Link]

Details2. Solute carrier organic anion transporter family member 1B3

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name: SLCO1B3
Uniprot ID: Q9NPD5
Uniprot Name: Solute carrier organic anion transporter family member 1B3
Molecular Weight: 77402.175 Da

References

CHMP Public Assessment Report: Linzagolix choline [Link]

Details3. Solute carrier family 22 member 8

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name: SLC22A8
Uniprot ID: Q8TCC7
Uniprot Name: Solute carrier family 22 member 8
Molecular Weight: 59855.585 Da

References

CHMP Public Assessment Report: Linzagolix choline [Link]

Details4. ATP-binding cassette sub-family G member 2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate
Curator comments: Only at high concentrations (significantly in excess of predicted clinical concentrations).

General Function: Xenobiotic-transporting atpase activity
Specific Function: High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name: ABCG2
Uniprot ID: Q9UNQ0
Uniprot Name: ATP-binding cassette sub-family G member 2
Molecular Weight: 72313.47 Da

References

CHMP Public Assessment Report: Linzagolix choline [Link]

Details5. Solute carrier family 22 member 6

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name: SLC22A6
Uniprot ID: Q4U2R8
Uniprot Name: Solute carrier family 22 member 6
Molecular Weight: 61815.78 Da

References

CHMP Public Assessment Report: Linzagolix choline [Link]

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

Linzagolix

Identification

Structure for Linzagolix (DB17083)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

Enzymes

References

References

References

Carriers

References

Transporters

References

References

References

References

References