Relugolix Chemical Properties

Melting point:

228 °C (decomp)(Solv: ethyl acetate (141-78-6); tetrahydrofuran (109-99-9))

Density 

1.442±0.06 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMSO:20.0(Max Conc. mg/mL);32.1(Max Conc. mM)
Ethanol:1.0(Max Conc. mg/mL);1.6(Max Conc. mM)

form 

A crystalline solid

pka

13.17±0.70(Predicted)

color 

White to off-white

InChI

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)

InChIKey

AOMXMOCNKJTRQP-UHFFFAOYSA-N

SMILES

N(C1=CC=C(C2SC3=C(C=2CN(C)C)C(=O)N(C2=NN=C(OC)C=C2)C(=O)N3CC2=C(F)C=CC=C2F)C=C1)C(NOC)=O

Relugolix Usage And Synthesis

Description

Relugolix (TAK-385) is a potent, orally active, nonpeptidic gonadotropin-releasing hormone (GnRH) antagonist. It possesses high affinity and potent antagonistic activity for human receptor (binding IC50=0.33 nM) and monkey receptor (IC50=0.32 nM) compared with TAK-013 (HY-100209). Relugolix is used for the study of sex-hormone-dependent diseases, such as including endometriosis, uterine fibroids and prostate cancer et al.

Uses

Relugolix is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment

Mechanism of action

The mechanism of action of relugolix is as a Gonadotropin Releasing Hormone Receptor Antagonist, and Cytochrome P450 3A Inducer, and Cytochrome P450 2B6 Inducer, and Breast Cancer Resistance Protein Inhibitor, and P-Glycoprotein Inhibitor. The physiologic effect of relugolix is by means of Decreased GnRH Secretion.

Pharmacokinetics

Relugolix is a selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (IC50 = 0.12 nM).A single oral administration of relugolix at a dose of 3 mg/kg has been found to suppress luteinizing hormone (LH) levels for more than 24 hours in castrated cynomolgus monkeys, indicating a long duration of action. The drug (80–160 mg/day) has been found to reduce testosterone levels to sustained castrate levels in men with once-daily administration.[8] Lower dosages (10–40 mg/day) are being studied in the treatment of endometriosis and uterine fibroids to achieve partial sex hormone suppression.  The reasoning behind partial suppression for these conditions is to reduce the incidence and severity of menopausal symptoms such as hot flushes and to avoid bone mineral density changes caused by estrogen deficiency that can eventually lead to osteoporosis.

Clinical Use

Relugolix was first approved in Japan in 2019, under the brand name Relumina, for the symptomatic treatment of uterine fibroids, and more recently by the United States' FDA in 2020, under the brand name Orgovyx, for the treatment of advanced prostate cancer. Relugolix has also been studied in the symptomatic treatment of endometriosis. 

Side effects

Common side effects of Relugolix include: hot flashes; flushing of the skin; sweating; weight gain or loss of ability; pain in the muscles, back, joints or bones; fatigue; diarrhoea; constipation; difficulty sleeping; depression; and breast enlargement. More serious side effects include: dizziness; fainting; rapid heartbeat; or chest pain; swelling of the face, lips, mouth or tongue; difficulty breathing or swallowing; rash; measles; redness of the skin; chest pain or tightness in the chest; or pain in the arms, back, neck or jaw; sudden numbness or weakness of the face, arms, or legs (especially on one side of the body); sudden blurred consciousness; difficulty speaking or understanding; sudden difficulty seeing with one or both eyes; or sudden difficulty walking, walking, or seeing with one or both eyes. or sudden difficulty walking, dizziness, loss of balance or coordination, etc.

Synthesis

Relugolix is produced by the reaction of 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione and phenyl N-methoxycarbamate.

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