834153-87-6 Usage
Pharmacodynamics
Elagolix acts as a potent and selective competitive antagonist of the gonadotropin-releasing hormone receptor (GnRHR), the biological target of the hypothalamic peptide hormone gonadotropin-releasing hormone (GnRH).As such, it is a GnRH antagonist.The affinity (KD) of elagolix for the GnRHR is 54 pM.By blocking the GnRHR in the pituitary gland, elagolix suppresses the GnRH-induced secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, and thereby decreases the production of sex hormones by the gonads. In women, elagolix dose-dependently suppresses the production of ovarian hormones including estradiol, progesterone, and testosterone, and thereby decreases the circulating levels of these hormones.
In men, GnRH modulators suppress the testicular production of testosterone and estradiol, decreasing the circulating levels of these hormones similarly. Unlike previous GnRH agonists and antagonists, referred to collectively as GnRH analogues, elagolix is a non-peptide and small-molecule compound that can be taken orally. Estrogens like estradiol stimulate the growth of the endometrium, and thereby aggravate symptoms of endometriosis.By suppressing estrogen production and levels, elagolix decreases the growth of the endometrium and decreases endometriosis symptoms such as pelvic pain.
Elagolix is a short-acting GnRH antagonist, with a terminal half-life of typically about 4 to 6 hours.Because of the short duration of elagolix in the body, the activation of the GnRHR by GnRH is not fully blocked throughout the day with once-daily administration of elagolix. As a result, gonadotropin and sex hormone levels are only partially suppressed when elagolix is taken once per day.In addition, the degree of suppression can be dose-dependently adjusted as needed, for instance with higher-dose twice-daily administration to achieve greater hormonal suppression.Because of its short duration in the body, the effects of elagolix are rapidly reversible upon discontinuation. In addition, due to its partial and incomplete suppression of estradiol levels, the side effects of elagolix, such as hot flashes and decreased BMD, are lower than with first-generation GnRH modulators.
Side effects
The side effects of elagolix are in general similar to menopausal symptoms.The most common side effects of elagolix (incidence ≥10%) are hot flashes, night sweats, headaches, nausea, and amenorrhea (cessation of menstruation). The next most frequent side effects of elagolix (incidence ≥5%) are insomnia, anxiety, arthralgia (joint pain), depression, and mood changes.Less common side effects of elagolix (incidence ≥3% and <5%) include decreased sex drive, diarrhea, abdominal pain, weight gain, dizziness, constipation, and irritability. Other common side effects of elagolix include decreased bone mineral density (BMD) and changes in the blood lipid profile. Rare but serious adverse effects that were observed during elagolix therapy in clinical trials included appendicitis (0.3%), abdominal pain (0.2%), and back pain (0.2%), though it is unknown if these were due to elagolix.Other serious adverse effects of elagolix may include bone loss, miscarriage, suicidality, and elevated liver enzymes.Elagolix was discontinued due to side effects by 5 to 10% of women in clinical trials, with the most common reasons being hot flashes or night sweats, nausea, and decreased BMD.
Elagolix dose- and duration-dependently decreases BMD in premenopausal women with long-term therapy. After 6 months of treatment with elagolix, lumbar spine BMD was decreased by 0.3 to 1.3% with 150 mg once per day and by 2.5 to 3.1% with 200 mg twice per day.The decrease in BMD during elagolix therapy may not be fully reversible with discontinuation, as only partial recovery was observed 12 months after discontinuation of therapy. The cause of the decrease in BMD with elagolix is estrogen deficiency, and is analogous to that associated with postmenopause.The consequences of the effects of elagolix on BMD are unknown, but may be an increase in the risk of bone loss and fractures.This is why the duration of use of elagolix should be limited. In women with risk factors for bone loss and osteoporosis, such as a history of low-trauma fracture, assessment of BMD may be considered. Elagolix should not be used in premenopausal women with known osteoporosis.Supplementation with calcium and/or vitamin D during treatment with elagolix has not been studied, but may be beneficial for helping to maintain bone health.
Contraindications
Contraindications of elagolix include pregnancy, known osteoporosis, severe hepatic impairment, and concomitant use with strong organic anion-transporting polypeptide (OATP) 1B1 inhibitors such as ciclosporin and gemfibrozil.Elagolix may increase the risk of miscarriage in early pregnancy.Women should avoid pregnancy while taking elagolix, for instance by using birth control, and should discontinue the medication if they become or wish to become pregnant. Elagolix should not be used in women with osteoporosis because it may increase the risk of further bone loss.
Severe hepatic impairment is associated with 7-fold increased exposure to elagolix, which may increase the risk of bone loss. In women with moderate hepatic impairment, which is associated with 3-fold increased exposure to elagolix, the medication at 200 mg twice per day should not be used, while 150 mg once per day should be used for no more than 6 months.OATP1B1 inhibitors are likely to greatly increase exposure to elagolix similarly to moderate to severe hepatic impairment.Combined birth control is not contraindicated with elagolix, but because of the estrogen component, is expected to decrease the effectiveness of elagolix in the treatment of endometriosis, and hence is not recommended.Other forms of birth control, such as non-hormonal birth control, can be used instead. Elagolix is not contraindicated in women who are breastfeeding, but it is unknown whether the medication is excreted in breast milk or if it has adverse effects on milk production or the breastfed child.The use of elagolix in women who are breastfeeding should be considered carefully, weighing both benefits and risks.
Preparation
Elagolix was a gonadotropin-releasing hormone antagonist. It was approved in 2018 by FDA via priority review for clinical treatment of endometriosis. Based on retrosynthetic analysis, five reported synthesis routes of elagolix were summarized. They were compared and evaluated in terms of step numbers, total yields, costs, synthetic conditions and manufacturing safety. At last, the synthetic method of d6-elagolix was introduced. This review would be beneficial to the future process researches of elagolix and its deuterium analogues.Recent Progress in the Synthesis of ElagolixDiscovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
Check Digit Verification of cas no
The CAS Registry Mumber 834153-87-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,3,4,1,5 and 3 respectively; the second part has 2 digits, 8 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 834153-87:
(8*8)+(7*3)+(6*4)+(5*1)+(4*5)+(3*3)+(2*8)+(1*7)=166
166 % 10 = 6
So 834153-87-6 is a valid CAS Registry Number.
834153-87-6Relevant articles and documents
Preparation method of Elagolix
-
Paragraph 0023-0035, (2019/05/02)
The invention discloses a preparation method of Elagolix. The method is characterized in that (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-diketone as shown in the formula II and 4-oxobutyric acid as shown in the formula V are subjected to a reductive amination reaction, and Elagolix as shown in the formula I is obtained; the formulas are defined in the description. The method has the advantages that a target product can be obtained through a one-step reaction, the synthetic route is greatly shortened, and the preparation process is simplified; the route has fewer side reactions, introduction of impurities is reduced, subsequent passivating treatment can be easy and convenient, and the purity of the target product is effectively improved.
Method for preparing agomelatine intermediate (by machine translation)
-
, (2019/12/09)
The invention relates to a method for preparing an intermediate of agomelatine. The method is simple and convenient to E8 operate, mild E8 in condition and very suitable for industrial production C. (by machine translation)
Method for preparing intermediate of elagolix
-
, (2019/12/09)
The invention relates to a method for preparing an intermediate of elagolix. In particular, the invention discloses a method for preparing a key intermediate compound E8 of elagolix, and compounds such as a compound E4 for preparing the intermediate compound E8. The method is simple and convenient in operation, mild in condition and very applicable to industrial production.
Synthetic method of elagolix
-
Page/Page column 7-11, (2019/06/11)
The invention discloses a synthetic method of elagolix. The synthetic method comprises the following steps that (1) (R)-(2-(5-(2-fluoro-3-methoxyphenyl))-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-diox-3,6-dihydropyrimidin-1(2H)-yl)-1-phenethyl)tert-butyl carbamate shown in a formula II is N-alkylated with ethyl 4-bromobutyrate shown in a formula IV to obtain an intermediate shown in a formula VI; (please see the specification for the formulae); and (2) the intermediate shown in the formula VI is subjected to de-N-BOC and O-Et to obtain Elagolix shown in the formula (I).(Please see the specification for the formula). The synthetic method of Elagolix has the advantages that the synthesis route is simple, by-products are few, and purification is easy.
Elagolix synthesis method
-
, (2018/10/11)
The invention provides an elagolix synthesis method. The elagolix synthesis method comprises enabling a compound 5 and a compound 10 to participate in a condensation reaction to finish N-alkylation reaction to obtain a compound 11, and then implementing alkaline hydrolysis to obtain elagolix 12. The invention further discloses two synthesis methods of the compound 5: the method I comprises enabling a 5-bromine-6-methylpyrimidine-2,4(1H,3H)-diketone compound 1 and a 2-(brooethyl)-1-fluorin-3-(trifluoromethyl) benzene compound 2 to have a condensation reaction to obtain an intermediate 3, and then having a coupling reaction; the method II comprises enabling 1-halide-3-fluorin-2-anisole and acetoacetate 7 to have a coupling reaction to obtain a compound 8, and then having a condensation cyclization reaction with a compound 9; the improvements greatly shorten the route steps, the route efficiency is improved, the use of a noble metal catalyst is avoided, and the process cost is greatly lowered. The operation of the route is simple, the total yield is high, the purity of an obtained product is also relatively high, and the method is suitable for the enlarged production.
Deuterated elagolix derivative and use thereof
-
, (2018/07/06)
The invention discloses a method for preparing a deuterated elagolix derivative. When being used as a GnRH receptor antagonist, the deuterated elagolix derivative has the use of treating disease states relevant to male and female sex hormone. The invention also discloses a composition containing the compound combined with a medicine acceptable carrier, and a method for antagonizing intraindividualgonadotropin to release hormone by using the composition.
PROCESSES FOR THE PREPARATION OF URACIL DERIVATIVES
-
Page/Page column 17, 18, (2009/06/27)
The present invention relates to processes and intermediates for preparing Gonadotropin-Releasing Hormone (GnRH) receptor antagonists of structure (VI); and stereoisomers and pharmaceutically acceptable salts thereof.
Discovery of sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6- [trifluoromethyl]-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl] -1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
Chen, Chen,Wu, Dongpei,Guo, Zhiqiang,Xie, Qiu,Reinhart, Greg J.,Madan, Ajay,Wen, Jenny,Chen, Takung,Huang, Charles Q.,Chen, Mi,Chen, Yongsheng,Tucci, Fabio C.,Rowbottom, Martin,Pontillo, Joseph,Zhu, Yun-Fei,Wade, Warren,Saunders, John,Bozigian, Haig,Struthers, R. Scott
experimental part, p. 7478 - 7485 (2009/12/07)
The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl) -4-methyl-2,6-dioxo-3,6-dihy-dro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
PYRIMIDINE-2, 4-DIONE DERIVATIVES AS GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS
-
Page 29-30, (2010/02/10)
GnRH receptor antagonists are disclosed that have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein R1a, R1b, R1c, R2a, R2b, R3, R4, R5, R6 and X are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
