Relugolix (TAK-385)
(Synonyms: 瑞卢戈利; TAK-385) 目录号 : GC32934
A GnRH receptor antagonist
Cas No.:737789-87-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
TAK-385 is an orally bioavailable gonadotropin-releasing hormone receptor (GnRHR) antagonist (IC50s = 0.33 and 0.32 nM for the human and monkey receptors, respectively).1 It is selective for these receptors over the rat GnRHR receptor (IC50 = 9,800 nM), as well as a panel of 134 enzymes and receptors at 10 ?M. TAK-385 is 95-fold more potent at inhibiting GnRH-induced arachidonic acid release in CHO cells expressing human GnRHR compared with those expressing monkey GnRHR. It decreases testis, ventral prostate, ovary, and uterus weight in human GNRHR knock-in mice when administered at doses ranging from 3 to 200 mg/kg per day for 28 days.2 TAK-385 (1 and 3 mg/kg) also decreases plasma luteinizing hormone levels in castrated cynomolgus monkeys.1
1.Miwa, K., Hitaka, T., Imada, T., et al.Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptorJ. Med. Chem.54(14)4998-5012(2011) 2.Nakata, D., Masaki, T., Tanaka, A., et al.Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: Studies in human GnRH receptor knock-in miceEur. J. Pharmacol.723167-174(2014)
| Cas No. | 737789-87-6 | SDF | |
| 别名 | 瑞卢戈利; TAK-385 | ||
| Canonical SMILES | O=C(NOC)NC1=CC=C(C(S2)=C(CN(C)C)C(C(N3C4=NN=C(OC)C=C4)=O)=C2N(CC5=C(F)C=CC=C5F)C3=O)C=C1 | ||
| 分子式 | C29H27F2N7O5S | 分子量 | 623.63 |
| 溶解度 | DMSO : 50 mg/mL (80.18 mM) | 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 | 1.6035 mL | 8.0176 mL | 16.0351 mL |
| 5 mM | 0.3207 mL | 1.6035 mL | 3.207 mL |
| 10 mM | 0.1604 mL | 0.8018 mL | 1.6035 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。
Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy
N Engl J Med 2021 Feb 18;384(7):630-642.PMID:33596357DOI:10.1056/NEJMoa2008283.
Background: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of Relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. Methods: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, Relugolix combination therapy (40 mg of Relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed Relugolix combination therapy (40 mg of Relugolix monotherapy, followed by Relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the Relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. Results: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the Relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both Relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with Relugolix combination therapy and placebo. Bone mineral density was similar with Relugolix combination therapy and placebo but decreased with Relugolix monotherapy. Conclusions: Once-daily Relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).
Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer
N Engl J Med 2020 Jun 4;382(23):2187-2196.PMID:32469183DOI:10.1056/NEJMoa2004325.
Background: Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of Relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known. Methods: In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive Relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients. Results: A total of 622 patients received Relugolix and 308 received leuprolide. Of men who received Relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of Relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of Relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with Relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the Relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the Relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88). Conclusions: In this trial involving men with advanced prostate cancer, Relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.).
Relugolix for the treatment of uterine fibroids
Expert Opin Pharmacother 2020 Oct;21(14):1667-1674.PMID:32674616DOI:10.1080/14656566.2020.1787988.
Introduction: Uterine fibroids (UF) are benign tumors common in premenopausal women, with strong impact on the health-care systems. For many years, surgery represented the only therapy for symptomatic fibroids. However, clinicians are observing a switch from surgery to noninvasive methods; in particular, medical treatment has been shown to be efficacious in obtaining a bleeding reduction and in ameliorating patient conditions. Areas covered: The authors review the current options available for the treatment of women with UF, with a special focus on the newest one, Relugolix. It is an orally active non-peptide Gonadotropin-releasing hormone (GnRH)-receptor antagonist recently licensed for women with symptomatic fibroids. Relugolix is a well-tolerated safe drug; it is effective in inducing a dose-dependent decrease in menstrual blood loss, with faster reduction of heavy menstrual bleeding (HMB) and a greater shrinkage in fibroid volume compared to the current standard of GnRH agonist treatment. Expert opinion: Relugolix is a promising drug for the non-surgical treatment of women with UF. To date, the only published data come from a well-selected Japanese female population study while results from worldwide ongoing studies are ongoing in order to confirm the efficacy of this GnRH agonist receptor.
Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose-response manner: a randomized, double-blind, placebo-controlled study
Fertil Steril 2021 Feb;115(2):397-405.PMID:32912633DOI:10.1016/j.fertnstert.2020.07.055.
Objective: To evaluate the efficacy and safety of three dose levels of Relugolix, a gonadotropin-releasing hormone receptor antagonist, compared with placebo and leuprorelin in women with endometriosis-associated pain. Design: Phase 2, multicenter, randomized, double-blind, placebo-controlled study. Setting: Hospitals and clinics. Patient(s): Adult premenopausal women with endometriosis who had dysmenorrhea and endometriosis-associated pelvic pain. Intervention(s): During a 12-week treatment period, patients received Relugolix 10 mg (n = 103), 20 mg (n = 100), or 40 mg (n = 103) as a daily oral dose; placebo (n = 97) as a daily oral dose; or leuprorelin 3.75 mg (n = 80) as a monthly subcutaneous injection. Main outcome measure(s): Primary endpoint was the change from baseline in mean visual analog scale score for pelvic pain during 28 days before the end of treatment. Result(s): The mean changes in mean visual analog scale score for pelvic pain were -3.8 mm in the placebo group; -6.2, -8.1, and -10.4 mm in the Relugolix 10-mg, 20-mg, and 40-mg groups; respectively; and -10.6 mm in the leuprorelin group. The major adverse events with Relugolix were hot flush, metrorrhagia, menorrhagia, and irregular menstruation, and bone mineral density decrease in a dose-response manner, which were also observed in the leuprorelin group with a frequency comparable with that in the Relugolix 40-mg group. Conclusion(s): Oral administration of Relugolix alleviated endometriosis-associated pain in a dose-response manner and was generally well tolerated. Relugolix 40 mg demonstrated efficacy and safety comparable with those of leuprorelin. Clinical trial registration number: NCT01458301.
Relugolix Combination Therapy for Uterine Leiomyoma-Associated Pain in the LIBERTY Randomized Trials
Obstet Gynecol 2022 Jun 1;139(6):1070-1081.PMID:35675604DOI:10.1097/AOG.0000000000004787.
Objective: To assess the effect of once-daily Relugolix combination therapy (relugolix-CT: Relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg) compared with placebo on moderate-to-severe pain in women with uterine leiomyomas and heavy menstrual bleeding. Methods: Two replicate, multinational, double-blind, 24-week, randomized, phase 3 studies (LIBERTY 1 and 2) were conducted in premenopausal women with uterine leiomyoma-associated heavy menstrual bleeding (80 mL or greater per cycle for two cycles or 160 mL or greater during one cycle). A predefined secondary objective was to determine the effect of relugolix-CT on moderate-to-severe uterine leiomyoma-associated pain in the pain subpopulation (women with maximum pain scores of 4 or higher on the 0-10 numerical rating scale at baseline, with pain score reporting compliance of 80% (ie, 28 days or more over the last 35 days of treatment). This key secondary endpoint was defined as the proportion of women achieving minimal-to-no uterine leiomyoma-associated pain (maximum numerical rating scale score 1 or lower) at week 24; menstrual and nonmenstrual pain were evaluated in prespecified secondary analyses. Treatment comparisons were performed in the pooled LIBERTY 1 and 2 pain subpopulation using the Cochran-Mantel-Haenszel test stratified by baseline menstrual blood loss volume. Results: Across both trials, 509 women were randomized to relugolix-CT or placebo (April 2017-December 2018). Of these, 277 (54.4%) met pain subpopulation requirements. With relugolix-CT, 45.2% (95% CI 36.4-54.3) of women achieved minimal-to-no pain compared with 13.9% (95% CI 8.8-20.5) with placebo (nominal P<.001). The proportions of women with minimal-to-no pain during menstrual days and during nonmenstrual days were significantly higher with relugolix-CT (65.0% [95% CI 55.6-73.5] and 44.6% [95% CI 32.3-57.5], respectively) compared with placebo (19.3% [95% CI 13.2-26.7], nominal P<.001, and 21.6% [95% CI 12.9-32.7], nominal P=.004, respectively). Conclusion: Over 24 weeks, relugolix-CT significantly reduced moderate-to-severe uterine leiomyoma-associated pain with a more pronounced effect on menstrual pain. These data support that relugolix-CT had clinically meaningful effects on women's experience of uterine leiomyoma-associated pain. Clinical trial registration: ClinicalTrials.gov: LIBERTY 1, NCT03049735; LIBERTY 2, NCT03103087. Funding source: Myovant Sciences GmbH.