Absorption, Distribution and Excretion
Linzagorgide is rapidly absorbed after oral administration, with peak plasma concentration (Cmax) occurring approximately 2 hours after administration. Linzagorgide is primarily excreted in the urine, with about one-third excreted in the feces. After 7 consecutive days of oral administration of 100 mg or 200 mg linzagorgide, the volumes of distribution were 11.067 L and 11.178 L, respectively. After multiple oral administrations of 100 mg or 200 mg linzagorgide, the geometric mean apparent clearances were 0.522 L/h and 0.499 L/h, respectively. Metabolites/Metabolites Up to seven linzagorgide metabolites have been quantitatively detected in patient plasma, urine, and feces, but plasma metabolites account for less than 10% of total linzagorgide exposure. Two major demethylated metabolites—KP017 and KP046—have been identified. CYP2C9 is primarily responsible for the formation of KP017, while CYP2C8, CYP2C9, and CYP3A4 are primarily responsible for the formation of KP046. The unchanged parent drug is a major circulating component in human plasma and urine, and is also one of the major components in feces.

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Biological Half-Life
After multiple administrations, the half-life of linzagori is approximately 15 hours.

Protein Binding

Linzagolix is highly bound to proteins (>99%) in plasma, primarily 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 gonadotropin-releasing hormone (GnRH) receptor antagonist. It has been investigated for the treatment of estrogen-dependent conditions such as uterine fibroids and endometriosis. It is similar to other GnRH receptor antagonists such as cetrorelix, rilugolix, and ilagolix. Over 70% of women of reproductive age have uterine fibroids, and when symptoms occur, they are often accompanied by heavy menstrual bleeding, anemia, abdominal pain and bloating, bloating, urinary frequency, and reproductive dysfunction. Because these fibroids are inherently estrogen-dependent, hormone therapy that inhibits estrogen activity (including GnRH receptor antagonists like linzagolix) is thought to benefit from preventing the growth of endometrial glands within the myometrium. In June 2022, Linzagolix was approved in the European Union for the treatment of symptoms caused by uterine fibroids. Linzagolix is an orally bioavailable gonadotropin-releasing hormone (GnRH or LHRH) receptor antagonist with potential hormone-suppressing activity. After oral administration of Linzagolix, the drug competes with GnRH receptor binding sites, inhibiting signaling of GnRH receptors in the anterior pituitary gland, thereby suppressing the secretion and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In men, inhibition of LH secretion prevents the release of testosterone. Therefore, this may alleviate symptoms associated with hormone-dependent disorders such as hormone-dependent prostate cancer. In women, this can suppress ovarian estrogen production and may alleviate symptoms of sex hormone-dependent disorders such as pain, menorrhagia, or uterine fibroids caused by endometriosis.
See also: Linzagolix Choline (active ingredient).
Indications

Linzagolix is indicated for the treatment of moderate to severe uterine fibroids in women of reproductive age.
Yselty is indicated for the treatment of moderate to severe uterine fibroids in women of reproductive age.
Mechanism of Action

Linzagolix is a selective gonadotropin-releasing hormone (GnRH) receptor antagonist. It competitively binds to GnRH receptors in the pituitary gland, thereby inhibiting endogenous signal transduction and consequently suppressing the hypothalamic-pituitary-gonadal axis. More specifically, inhibition of GnRH signaling leads to suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) signaling, with FSH responsible for stimulating the ovaries to produce estrogen. Therefore, Linzagolix indirectly inhibits estrogen production and signal transduction, making it suitable for treating estrogen-dependent diseases such as 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.)