352290-60-9

Usage

Uses

Used in Pharmaceutical Industry:
NBI-42902 is used as a therapeutic agent for the treatment of neuropathic pain and drug addiction. Its selective antagonism of the NOP receptor helps in reducing pain and drug-seeking behavior, offering a potential solution for patients suffering from these conditions.
Used in Pain Management:
NBI-42902 is used as a pain modulator for neuropathic pain. By blocking the binding of orphanin FQ/nociceptin at the NOP receptor, it effectively reduces pain sensations and provides relief to patients experiencing chronic pain.
Used in Addiction Treatment:
NBI-42902 is used as an addiction treatment agent, targeting the NOP receptor to reduce drug-seeking behavior. Its ability to modulate addiction-related behaviors makes it a promising candidate for the treatment of drug addiction, helping patients overcome their dependence on substances.
Used in Preclinical Research:
NBI-42902 is used as a research tool in preclinical studies to investigate the role of the NOP receptor in pain modulation and addiction-related behaviors. Its selective antagonism allows researchers to better understand the mechanisms involved in these conditions and explore potential therapeutic interventions.

Upstream product

• 830346-53-7 3-[2(R)-(tert-butoxycarbonylamino)-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2,6-difluorobenzyl]-6-methylpyrimidine-2,4(1H,3H)-dione 
• 352303-69-6 {(R)-2-[5-bromo-3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester 
• 352303-66-3 5-bromo-1-(2,6-difluoro-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 
• 67341-01-9 (R)-N-(tert-butoxycarbonyl)phenylglycinol 

Downstream Products

• 830346-53-7 3-[2(R)-(tert-butoxycarbonylamino)-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2,6-difluorobenzyl]-6-methylpyrimidine-2,4(1H,3H)-dione 

Relevant academic research and scientific papers

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

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

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 formula (I) wherein R1a, R1b, R2a, R2b, R3, R4, R5, R6, R7 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.

PYRIMIDINE-2, 4-DIONE DERIVATIVES AS GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS

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.

GONADOTROPIN-RELEASING HORMONE RECEPTOR ANTAGONISTS AND METHODS RELATING THERETO

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 n, 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.

3-[(2R)-amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3- methoxyphenyl)-6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization

Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6- difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-di-one (R-13b, NBI 42902) displayed subnanomolar binding affinity (Ki = 0.56 nM) and was a potent functional antagonist (IC50 = 3.0 nM in Ca 2+ flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (Ki = 3.9 nM). In addition, R-13b had good plasma exposure in cynomolgus monkeys after oral administration, with a Cmax of 737 ng/mL and an AUC of 2392 ng/mL·h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.