Linzagolix
(Synonyms: 林扎戈利,KLH-2109; OBE-2109) 目录号 : GC63884
Linzagolix (KLH-2109; OBE-2109) 是一种有效的，非多肽，口服有效的 GnRH 拮抗剂。可用于子宫肌瘤、子宫内膜异位症、子宫腺肌症研究。
Cas No.:935283-04-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Linzagolix (KLH-2109; OBE-2109) is a potent, non-peptide, and orally active GnRH antagonist. Linzagolix can be used for uterine fibroids, endometriosis, adenomyosis research[1].
[1]. Susan Dababou, et al. 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.
| Cas No. | 935283-04-8 | SDF | Download SDF |
| 别名 | 林扎戈利,KLH-2109; OBE-2109 | ||
| 分子式 | C22H15F3N2O7S | 分子量 | 508.42 |
| 溶解度 | DMSO : 125 mg/mL (245.86 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9669 mL | 9.8344 mL | 19.6688 mL |
| 5 mM | 0.3934 mL | 1.9669 mL | 3.9338 mL |
| 10 mM | 0.1967 mL | 0.9834 mL | 1.9669 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Linzagolix: First Approval
Drugs 2022 Aug;82(12):1317-1325.PMID:35997940DOI:10.1007/s40265-022-01753-9.
Linzagolix (Yselty®) is an orally administered, selective, non-peptide small molecule gonadotrophin releasing hormone (GnRH) receptor antagonist that is being developed by Kissei Pharmaceutical for the treatment of uterine fibroids and endometriosis in women of reproductive age. Linzagolix binds to and blocks the GnRH receptor in the pituitary gland, modulating the hypothalamic pituitary-gonadal axis and dose-dependently reducing serum luteinising hormone and follicle-stimulating hormone production and serum estradiol levels. In June 2022, Linzagolix was approved for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age in the EU. Linzagolix is under regulatory review the USA for this indication and is in phase 3 clinical development in the treatment of pain associated with endometriosis. This article summarizes the milestones in the development of Linzagolix leading to this first approval for the treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.
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.PMID:34278887DOI:10.1080/13543784.2021.1957830.
Introduction: Uterine myomas and endometriosis are benign hormone-dependent diseases affecting women of reproductive age. Substantial efforts have been made to develop innovative medical options for treating these gynecologic diseases. Elagolix and relugolix have been approved in some countries for treating endometriosis and myomas, respectively; however, Linzagolix (OBE 2109, KLH 2109) is a new oral gonadotropin-releasing hormone (GnRH) antagonist in phase II-III trials. Treatment options for women with contraindications for hormonal therapies or who refuse particular options, are the driving force behind the development of new drugs in this area. Area covered: This drug evaluation highlights definitive and preliminary results from previous and ongoing studies of Linzagolix for the treatment of endometriosis and myomas. Expert opinion: Linzagolix showed a dose-dependent and rapidly reversible action on the pituitary-gonadal axis. In a recent phase II trial (EDELWEISS), Linzagolix significantly reduced pain related to endometriosis and improved quality of life at single daily doses of 75-200 mg. The preliminary results of international, double-blind phase III trials (PRIMROSE 1 and 2) reported its efficacy in treating heavy menstrual bleeding related to myomas with a good safety profile. Further studies will determine the necessity of add-back therapy during long-term use of Linzagolix.
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.PMID:32505383DOI:10.1016/j.fertnstert.2020.02.114.
Objective: To study the effect of a new investigational oral gonadotropin-releasing hormone antagonist, Linzagolix, on endometriosis-associated pain (EAP). Design: A multinational, parallel group, randomized, placebo-controlled, double-blind, dose-ranging trial. Setting: Clinical centers. Patient(s): Women aged 18-45 years with surgically confirmed endometriosis and moderate-to-severe EAP. Intervention(s): The interventions were 50, 75, 100, or 200 mg Linzagolix (or matching placebo) administered once daily for 24 weeks. Main outcome measure(s): The primary endpoint was the number of responders (≥30% reduction in overall pelvic pain) after 12 weeks. Other endpoints included dysmenorrhea, non-menstrual pelvic pain, serum estradiol, amenorrhea, quality of life (QoL) measures, and bone mineral density (BMD). Result(s): Compared with placebo, doses ≥ 75 mg resulted in a significantly greater proportion of responders for overall pelvic pain at 12 weeks (34.5%, 61.5%, 56.4%, and 56.3% for placebo, 75, 100, and 200 mg, respectively). A similar pattern was seen for dysmenorrhea and non-menstrual pelvic pain. The effects were maintained or increased at 24 weeks. Serum estradiol was suppressed, QoL improved, and the rate of amenorrhea increased in a dose-dependent fashion. Mean BMD loss (spine) at 24 weeks was <1% at doses of 50 and 75 mg and increased in a dose-dependent fashion up to 2.6% for 200 mg. BMD of femoral neck and total hip showed a similar pattern. Conclusion(s): Linzagolix significantly reduced EAP and improved QoL at doses of 75-200 mg and decreased BMD dose-dependently. Clinical trial registration number: NCT02778399.
Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials
Lancet 2022 Sep 17;400(10356):896-907.PMID:36116480DOI:10.1016/S0140-6736(22)01475-1.
Background: Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of Linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids. Methods: PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg Linzagolix per day alone, (3) 100 mg Linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg Linzagolix per day alone, or (5) 200 mg Linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed. Findings: Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all Linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with Linzagolix [200 mg] alone and 3-14% in all other groups). Interpretation: Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day Linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy. Funding: ObsEva.
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.PMID:35690889DOI:10.1111/1440-1681.13688.
Control of gonadotropin-releasing hormone (GnRH) signalling is an effective strategy for the treatment of sex hormone-dependent diseases. GnRH analogues have been widely used for treating these diseases; however, initial stimulation or complete suppression of GnRH signalling by GnRH analogues results in the occurrence of several distinct adverse effects. Accordingly, we aimed to discover small molecule GnRH antagonists with superior pharmacokinetic and pharmacodynamic profiles. Linzagolix is a potent, orally available, and selective GnRH antagonist. Here, we reported the pharmacological characterization of Linzagolix in vitro and in vivo. Linzagolix selectively binds to the GnRH receptor and inhibits GnRH-stimulated signalling, in a manner comparable to cetrorelix, a peptide GnRH antagonist. Because the inhibitory effect of the gonad axis is useful for the treatment of gynaecological conditions such as endometriosis and uterine fibroids, we investigated the effect of orally administrated Linzagolix on the gonadal axis in ovariectomized and intact cynomolgus monkeys. In ovariectomized monkeys, Linzagolix immediately suppressed the serum luteinizing hormone concentration at doses over 1 mg/kg, indicating dose-dependent inhibition that correlated with serum Linzagolix concentrations. In intact female monkeys, repeated Linzagolix administration suppressed hormone surges and ceased or prolonged menstrual cycles. Furthermore, all animals presenting arrested menstrual cycles following Linzagolix treatment showed recovery of hormone secretion and regular menstrual cycles after administration periods ended. Our results demonstrated that Linzagolix has potential as a novel agent for reproductive-age women suffering from sex hormone-dependent diseases.