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
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

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 TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Symptomatic treatment ofModerate uterine fibroids••••••••••••••••••••••••••••• •••••••••••••••• •••• ••••••
Symptomatic treatment ofSevere 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.

TargetActionsOrganism
AGonadotropin-releasing hormone receptor
antagonist
Humans
Absorption

Linzagolix is quickly absorbed following oral administration, with Cmax 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.
DrugInteraction
AlmotriptanThe serum concentration of Almotriptan can be increased when it is combined with Linzagolix.
AminophenazoneThe serum concentration of Aminophenazone can be increased when it is combined with Linzagolix.
AmiodaroneThe serum concentration of Amiodarone can be increased when it is combined with Linzagolix.
AmitriptylineThe serum concentration of Amitriptyline can be increased when it is combined with Linzagolix.
AmodiaquineThe 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
IngredientUNIICASInChI Key
Linzagolix cholineVHS6SC660Q1321816-57-2IAIVRTFCYOGNBW-UHFFFAOYSA-M
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
YseltyTablet, film coated200 mgOralTheramex Ireland Limited2023-05-04Not applicableEU flag
YseltyTablet, film coated100 mgOralTheramex Ireland Limited2022-07-15Not applicableEU flag
YseltyTablet, film coated100 mgOralTheramex Ireland Limited2023-05-04Not applicableEU flag
YseltyTablet, film coated200 mgOralTheramex Ireland Limited2022-07-15Not applicableEU flag

Categories

ATC Codes
H01CC04 — Linzagolix
Drug Categories
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]
ChemSpider
17590169
BindingDB
160329
RxNav
2621019
ChEMBL
CHEMBL3668014
ZINC
ZINC000043152963
Wikipedia
Linzagolix

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentEndometriosis1
3CompletedTreatmentEndometriosis1
3CompletedTreatmentHeavy Menstrual Bleeding / Uterine Fibroids (Leiomyomas)2
3TerminatedTreatmentEndometriosis2
2CompletedTreatmentEndometriosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Powder1 kg/1kg
Tablet, film coatedOral100 mg
Tablet, film coatedOral200 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySlightly solublehttps://www.ema.europa.eu/en/documents/assessment-report/yselty-epar-public-assessment-report_en.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.00198 mg/mLALOGPS
logP3.2ALOGPS
logP3.88Chemaxon
logS-5.4ALOGPS
pKa (Strongest Acidic)3.15Chemaxon
pKa (Strongest Basic)-3.5Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area114.4 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity117.25 m3·mol-1Chemaxon
Polarizability45.39 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
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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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]

Enzymes

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

Carriers

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

Transporters

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
  1. CHMP Public Assessment Report: Linzagolix choline [Link]
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
  1. CHMP Public Assessment Report: Linzagolix choline [Link]
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
  1. CHMP Public Assessment Report: Linzagolix choline [Link]
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
  1. CHMP Public Assessment Report: Linzagolix choline [Link]
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
  1. CHMP Public Assessment Report: Linzagolix choline [Link]

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