human GnRH ( IC50 = 0.33 nM ); monkey GnRH ( IC50 = 0.32 nM )
Human gonadotropin-releasing hormone receptor (GnRHR) antagonist (binding IC50 = 0.33 nM in the presence of serum).
Monkey GnRHR antagonist (binding IC50 = 0.32 nM).
Rat GnRHR (low affinity, binding IC50 = 9800 nM).

Relugolix 对猴受体表现出与人类受体 (IC50=0.33 nM) 相当的强结合亲和力 (IC50=0.32 nM)，而对大鼠受体 (IC50=9800 nM) 则降低了 30000 倍。在 40% 血清存在下，TAK-385 对人受体的体外拮抗活性 (IC90=18 nM) 比对猴受体 (IC90=1700 nM) 的拮抗活性高出 95 倍[1]。

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与先导化合物TAK-013相比，Relugolix对人和猴GnRH受体具有更高的亲和力和更强的拮抗活性。对人GnRHR的结合IC50为0.33 nM（在血清存在下），对猴GnRHR的结合IC50为0.32 nM。

Relugolix（口服；1-3 mg/kg；单剂量用于药代动力学研究）在 1 mg/kg 剂量下表现出良好的药代动力学特征和明显的对猴子循环 LH 水平的抑制作用。雄性食蟹猴的药代动力学曲线显示，Cmax、Tmax 和 AUCo 分别为 16.0 ng/mL、2.7 h 和 90.1 ng[1]。 Relugolix（口服；3、10 或 30 mg/kg；每天两次；4 周）显着降低男性睾丸重量，并在 3 mg/kg 时降低腹侧前列腺重量，在 10 mg/kg 时将其降低至去势水平hGNRHR 敲入小鼠[2]。 Relugolix（口服；30、100 或 200 mg/kg；每天两次；4 周）在 100 mg/kg 剂量的第一周内诱导所有小鼠持续绝情期，并在该剂量后显着降低卵巢和子宫的重量雌性 hGNRHR 敲入小鼠 4 周[2]。动物模型：雄性hGNRHR敲入小鼠[2] 剂量：3、10或30 mg/kg 给药方法：口服； 3、10或30毫克/公斤；每天两次; 4 周 结果：睾丸功能下降。动物模型：雌性 hGNRHR 敲入小鼠[2] 剂量：30、100 或 200 mg/kg 给药方法：口服；给药方式： 30、100或200毫克/公斤；每天两次; 4 周结果：将下丘脑-垂体-性腺轴抑制至性腺切除水平。垂体中 GnRH 受体 mRNA 水平下调。

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雄性人GnRHR敲入小鼠： 每日两次口服relugolix，持续4周，在10 mg/kg剂量下显著降低睾丸重量。在3 mg/kg剂量下即显著降低腹侧前列腺重量，在10 mg/kg剂量下可将其降至去势水平。[1]
雌性人GnRHR敲入小鼠： 每日两次口服relugolix（100 mg/kg）在第一周内诱导持续的动情间期。4周后，显著降低卵巢和子宫重量，降至与卵巢切除小鼠相当的水平。在有效抑制性腺功能的剂量下，垂体中GnRH受体mRNA的表达被下调。[1]
恢复研究： Relugolix的抑制作用是可逆的。在接受100或200 mg/kg每日两次给药28天的雌性小鼠中，停药后约5天动情周期恢复，降低的卵巢和子宫重量在停药后14天内完全恢复。[1]
在接受30 mg/kg每日两次给药28天的雄性小鼠中，腹侧前列腺重量和血清睾酮水平在停药后14天内从完全抑制状态恢复，但睾丸重量在28天观察期内未恢复。

Male hGNRHR-knock-in mice
3, 10 or 30 mg/kg
Oral administration; 3, 10 or 30 mg/kg; twice daily; 4 weeks

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Model: All efficacy studies were conducted in human GnRH receptor (hGNRHR) knock-in mice, where the mouse Gnrhr gene was replaced with human GNRHR cDNA.
Drug Formulation: Relugolix was dissolved in 0.5% methylcellulose solution containing 6 mg/mL citric acid monohydrate.
Male Mouse Studies: Compounds were administered orally (by gavage) twice daily (BID) for 4 weeks at specified doses. Organ weights (testes, ventral prostate) were evaluated at endpoint.
Female Mouse Studies: Compounds were administered orally twice daily for 4 weeks at specified doses. Estrous cycles were monitored via vaginal cytology. Organ weights (ovaries, uterus) and pituitary GnRHR mRNA expression were evaluated at endpoint.
Recovery Studies: After 28 days of twice-daily oral administration, drug treatment was stopped. Estrous cycles (females) and organ weights (both sexes) were monitored at specified time points post-withdrawal (e.g., days 3, 7, 10, 14, 28). Blood was collected from male mice for serum testosterone measurement.

Absorption, Distribution and Excretion
The Cmax and AUC of orally-administered relugolix increase proportionally following single doses - in contrast, with repeat dosing the AUC remains proportional to the dose while the Cmax increases greater than proportionally to the dose. Following the administration of 120mg once daily, the steady-state AUC and Cmax of relugolix were 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively. The absolute oral bioavailability of relugolix is approximately 12% and the median Tmax following oral administration is 2.25 hours.
Approximately 81% of an orally administered dose was recovered in the feces, of which 4.2% was unchanged parent drug, while 4.1% of the dose was recovered in the urine, of which 2.2% remained unchanged.
The average renal clearance of relugolix is 8 L/h with a total clearance of 26.4 L/h.

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Metabolism / Metabolites
Relugolix is metabolized mainly by the CYP3A subfamily of P450 enzymes, with a smaller contribution by CYP2C8.

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Biological Half-Life
The average effective half-life of relugolix is 25 hours, while the average terminal elimination half-life is 60.8 hours.

Hepatotoxicity
Relugolix therapy has been associated with serum aminotransferase elevations above 3 times the upper limit of normal (ULN) in 1% to 3% of patients and in similar proportions of patients receiving comparator agents such as leuprolide or degarelix. The serum enzyme elevations are generally mild and self-limited, resolving even without dose adjustment. ALT values above 5 times the ULN occur in less than 1% of patients, and episodes of ALT elevations with symptoms or jaundice were not observed in preregistration clinical trials of relugolix alone or in combination with estradiol and norethindrone. Since its approval and more widescale use, there have been no published reports of clinically apparent liver injury attributed to relugolix.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Protein Binding
Relugolix is 68-71% protein-bound in plasma, primarily to albumin and, to a lesser extent, α1-acid glycoprotein.

[1]. 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 Receptor. J. Med. Chem. 2011, 54, 14, 4998–5012

[2]. 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 mice. Eur J Pharmacol . 2014 Jan 15:723:167-74.

Pharmacodynamics
Approximately 56% of patients achieved castrate-level testosterone concentrations (<50 ng/dL) by day 4 of therapy and 97% of patients maintain these levels through 48 weeks of therapy. Relugolix requires once-daily oral administration to maintain the desired testosterone concentrations. Androgen deprivation therapies may prolong the QTc interval and should therefore be used with caution in patients having a high baseline risk of QTc prolongation, such as those with electrolyte abnormalities, congestive heart failure, or using other medications known to prolong the QTc interval. Based on its mechanism of action and data from animal studies, relugolix may result in fetal harm if administered to pregnant females - male patients with female partners should be advised to use effective contraception throughout therapy and for 2 weeks following cessation of therapy to prevent inadvertent fetal exposure.

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Relugolix (TAK-385) is an investigational, novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist. It is a thienopyrimidine derivative.[1]
It builds on previous work with TAK-013 (sufugolix) but possesses higher affinity for human and monkey GnRH receptors.[1]
Its low affinity for the rat GnRH receptor necessitated the use of human GnRHR knock-in mice for in vivo evaluation.[1]
The study demonstrates that daily oral administration of relugolix can potently, continuously, and reversibly suppress the hypothalamic-pituitary-gonadal axis in this humanized model.[1]
Relugolix is proposed as a potential therapeutic intervention for hormone-dependent diseases such as endometriosis, uterine fibroids, prostate cancer, and premenopausal breast cancer.[1]
The downregulation of pituitary GnRH receptor mRNA by relugolix may contribute to its pharmacological action beyond competitive receptor antagonism.

C29H27F2N7O5S

623.630391359329

623.18

C, 55.85; H, 4.36; F, 6.09; N, 15.72; O, 12.83; S, 5.14

737789-87-6

Relugolix-d6

10348973

White to off-white solid powder

3.966

169.36

2

11

9

44

1010

0

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

AOMXMOCNKJTRQP-UHFFFAOYSA-N

InChI=1S/C29H27F2N7O5S/c1-36(2)14-19-24-26(39)38(22-12-13-23(42-3)34-33-22)29(41)37(15-18-20(30)6-5-7-21(18)31)27(24)44-25(19)16-8-10-17(11-9-16)32-28(40)35-43-4/h5-13H,14-15H2,1-4H3,(H2,32,35,40)

1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea

TAK 385; TAK385; TAK-385; trade names: Orgovyx; Relumina

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: 61~100 mg/mL (97.8~160.4 mM)

配方 1 中的溶解度: ≥ 0.83 mg/mL (1.33 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 8.3 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 0.83 mg/mL (1.33 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 8.3 mg/mL 澄清 DMSO 储备液加入 900 μL 20% SBE-β-CD 生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 0.83 mg/mL (1.33 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 8.3 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。