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Purity: ≥98%
Relugolix (formerly TAK-385; TAK385; trade names: Orgovyx and Relumina) is a non-peptidyl and orally bioactive antagonist of gonadotropin-releasing hormone (GnRH) approved in 2020 for use in the treatment of prostate cancer in men and uterine fibroids in women. It is also being developed as an endometriosis treatment. Relugolix inhibits GnRH in the presence of 40% fetal bovine serum with an IC50 of 0.33 nM. When compared to TAK-013, it has a stronger antagonistic activity and a higher affinity. While TAK-385 regulates the effects of LH and FSH on the ovary and lowers blood levels of estrogen, which are known to be linked to the development of endometriosis and uterine fibroids, Relugolix inhibits LH-RH from binding with the LH-RH receptor in the anterior pituitary gland and suppresses the secretion of luteinizing hormone (LH) and follicle stimulation hormone (FSH) from the anterior pituitary gland.
| Targets |
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). |
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| ln Vitro |
Relugolix shows a 30000-fold decrease for the rat receptor (IC50=9800 nM) but a strong binding affinity (IC50=0.32 nM) for the monkey receptor, which is comparable to that of the human receptor (IC50=0.33 nM). In the presence of 40% serum, TAK-385's antagonistic in vitro activity against the human receptor (IC90=18 nM) was 95 times greater than that against the monkey receptor (IC90=1700 nM)[1].
Relugolix possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared to its predecessor TAK-013. The binding IC50 for human GnRHR is 0.33 nM (in the presence of serum) and for monkey GnRHR is 0.32 nM. |
| ln Vivo |
Relugolix (oral administration; 1-3 mg/kg; single dose for pharmacokinetic study) shows clear suppression of circulating LH levels in monkeys at a dose of 1 mg/kg and a good pharmacokinetic profile. Male cynomolgus monkeys show a pharmacokinetic profile with Cmax, Tmax, and AUCo values of 16.0 ng/mL, 2.7 h, and 90.1 ng, respectively[1].
Relugolix (oral administration; 3, 10, or 30 mg/kg; twice daily; 4 weeks) dramatically lowers the weight of the testicles, lowers the weight of the ventral prostate (3 mg/kg), and lowers the weight of the prostate to castrate levels (10 mg/kg) in male hGNRHR-knock-in mice[2]. Relugolix (oral administration; 30, 100, or 200 mg/kg; twice daily; 4 weeks) causes all mice to enter a constant diestrous phase during the first week at 100 mg/kg, and after 4 weeks in female hGNRHR-knock-in mice, this dose significantly reduces the weights of the uteri and ovaries[2]. Male Human GnRHR Knock-in Mice: Twice-daily oral administration of relugolix for 4 weeks significantly decreased testis weight at 10 mg/kg. It significantly reduced ventral prostate weight at 3 mg/kg and decreased it to castrate levels at 10 mg/kg.[1] Female Human GnRHR Knock-in Mice: Twice-daily oral administration of relugolix at 100 mg/kg induced constant diestrous phases within the first week. After 4 weeks, it significantly decreased the weights of ovaries and uteri to levels comparable to ovariectomized mice. The expression of GnRH receptor mRNA in the pituitary was downregulated at doses effective in suppressing gonadal function.[1] Recovery Studies: The suppressive effect of relugolix was reversible. In female mice treated with 100 or 200 mg/kg twice daily for 28 days, estrous cycles resumed approximately 5 days after drug withdrawal, and the decreased weights of ovaries and uteri completely recovered within 14 days after withdrawal.[1] In male mice treated with 30 mg/kg twice daily for 28 days, the ventral prostate weight and serum testosterone levels recovered from a completely suppressed state within 14 days after drug withdrawal, although testis weight did not recover within the 28-day observation period. |
| Animal Protocol |
Male hGNRHR-knock-in mice
3, 10 or 30 mg/kg Oral administration; 3, 10 or 30 mg/kg; twice daily; 4 weeks 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. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
Following a single oral dose of regrugolide, its Cmax and AUC increase proportionally; conversely, with repeated dosing, AUC remains dose-proportional, while the increase in Cmax is greater than dose-proportional. After a once-daily dose of 120 mg, the steady-state AUC and Cmax of regrugolide are 407 (± 168) ng·hr/mL and 70 (± 65) ng/mL, respectively. The absolute oral bioavailability of regrugolide is approximately 12%, and the median time to peak concentration (Tmax) after oral administration is 2.25 hours. Approximately 81% of the oral dose is excreted in feces, of which 4.2% is unchanged; 4.1% is excreted in urine, of which 2.2% is unchanged. The mean renal clearance of regrugolide is 8 L/h, and the total clearance is 26.4 L/h. Metabolism/Metabolites Relugoline is primarily metabolized by the P450 enzyme CYP3A subfamily, with a smaller contribution from CYP2C8. Biological Half-Life The average effective half-life of relugoline is 25 hours, and the average terminal elimination half-life is 60.8 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In patients receiving regorafenib, 1% to 3% experienced serum transaminase elevations exceeding 3 times the upper limit of normal (ULN), a similar proportion observed in patients receiving control drugs such as leuprorelin or degarelix. Serum enzyme elevations are usually mild and self-limiting, resolving spontaneously even without dose adjustment. Less than 1% of patients had ALT values exceeding 5 times the ULN. No symptomatic or jaundice-related ALT elevations were observed in pre-registration clinical trials of regorafenib monotherapy or in combination with estradiol and norethindrone. Since its approval and widespread use, there have been no published reports of clinically significant liver injury caused by regorafenib. Probability Score: E (Unlikely a cause of clinically significant liver injury). Protein Binding Regorafenib has a protein binding rate of 68-71% in plasma, primarily binding to albumin, and secondarily to α1-acid glycoprotein. |
| References |
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| Additional Infomation |
Pharmacodynamics
Approximately 56% of patients achieved castration-level testosterone concentrations (<50 ng/dL) by day 4 of treatment, and 97% maintained this level during the 48-week treatment period. Relugoli needs to be taken orally once daily to maintain the required testosterone concentration. Androgen deprivation therapy may prolong the QTc interval; therefore, caution should be exercised in patients at high risk of baseline QTc interval prolongation, such as those with electrolyte disturbances, congestive heart failure, or those taking other medications known to prolong the QTc interval. Based on its mechanism of action and animal studies, use of relugolix in pregnant women may cause fetal harm—male patients with female partners should be advised to use effective contraception throughout treatment and for 2 weeks after discontinuation of treatment to prevent unintended fetal exposure. Relugolix (TAK-385) is an investigational novel non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist. It is a thienopyrimidine derivative. [1] It is based on previous studies of TAK-013 (shufogoli), but has a higher affinity for human and monkey GnRH receptors. [1] Due to its low affinity for rat GnRH receptors, in vivo evaluation using human GnRH receptor knock-in mice is required. [1] This study shows that daily oral administration of relugolix can effectively, persistently and reversibly inhibit the hypothalamic-pituitary-gonadal axis in this humanized model. [1] relugolix is considered 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 be another pharmacological mechanism of action besides competitive receptor inhibition. Hostile. |
| Molecular Formula |
C29H27F2N7O5S
|
|---|---|
| Molecular Weight |
623.630391359329
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| Exact Mass |
623.18
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| Elemental Analysis |
C, 55.85; H, 4.36; F, 6.09; N, 15.72; O, 12.83; S, 5.14
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| CAS # |
737789-87-6
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| Related CAS # |
Relugolix-d6
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| PubChem CID |
10348973
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| Appearance |
White to off-white solid powder
|
| LogP |
3.966
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
44
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| Complexity |
1010
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| Defined Atom Stereocenter Count |
0
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| 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
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| InChi Key |
AOMXMOCNKJTRQP-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
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
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| Synonyms |
TAK 385; TAK385; TAK-385; trade names: Orgovyx; Relumina
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 61~100 mg/mL (97.8~160.4 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.83 mg/mL (1.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 0.83 mg/mL (1.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 8.3 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 0.83 mg/mL (1.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 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 | 3.2070 mL | |
| 10 mM | 0.1604 mL | 0.8018 mL | 1.6035 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
LIBERTY 1: An International Phase 3 Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate Relugolix Co Administered with and without Low-Dose Estradiol and Norethindrone Acetate in Women with Heavy Menstrual Bleeding Associated with Uterine Fibroids
CTID: null
Phase: Phase 3 Status: Completed
Date: 2017-06-12
Products are for research use only; We do not sell to patients
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