Absorption, Distribution and Excretion
Linzagolix is quickly absorbed following oral administration, with Cmax occurring approximately 2 hours following administration.
Linzagolix is primarily excreted in the urine, with approximately one-third eliminated via the feces.
After seven days of oral administration of linzagolix 100mg or 200mg, the volume of distribution was 11.067 L and 11.178 L, respectively.
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.

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Metabolism / Metabolites
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. 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. Unchanged parent drug is the predominant circulating component in human plasma and in the urine, and one of the major components in the feces.

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Biological Half-Life
The half-life of linzagolix following multiple doses is approximately 15 hours.

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

[1]. 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.

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. 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. 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. Linzagolix was approved for use in the European Union in June 2022 for the management of symptoms caused by uterine fibroids.
Linzagolix is an orally bioavailable gonadotropin-releasing hormone (GnRH or LHRH) receptor antagonist, with potential hormone production inhibitory activity. Upon oral administration of linzagolix, this agent competes with GnRH for receptor binding and inhibits GnRH receptor signaling in the anterior pituitary gland, thereby inhibiting the secretion and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). In males, the inhibition of LH secretion prevents the release of testosterone. As a result, this may relieve symptoms associated with hormonally dependent disease states such as hormone-dependent prostate cancer. In women, this prevents the production of estrogen by the ovaries and may relieve symptoms from sex-hormone dependent diseases, such as pain associated with endometriosis, heavy menstrual bleeding or uterine fibroids.
See also: Linzagolix Choline (active moiety of).

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

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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. 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. Linzagolix, therefore, indirectly suppresses estrogen production and signaling, making it useful in the management of estrogen-dependent conditions like uterine fibroids.

C22H15F3N2O7S

508.42

508.055

C, 51.97; H, 2.97; F, 11.21; N, 5.51; O, 22.03; S, 6.31

935283-04-8

935283-04-8 (free);1321816-57-2 (choline);

16656889

White to light brown solid powder

1.6±0.1 g/cm3

1.621

3.07

2

11

7

35

826

0

S1C=C2C(=C1C(=O)O)C(N(C(N2)=O)C1C(=CC(=C(C=1)OCC1C(=C(C=CC=1OC)F)F)OC)F)=O

BMAAMIIYNNPHAB-UHFFFAOYSA-N

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)

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

KLH-2109; OBE-2109; KLH2109; OBE2109; KLH 2109; OBE 2109; trade name Yselty

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~245.86 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)