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, Dongpei Wu, Zhiqiang Guo, Qiu Xie, Greg J Reinhart, Ajay Madan, Jenny Wen, Takung Chen, Charles Q Huang, Mi Chen, Yongsheng Chen, Fabio C Tucci, Martin Rowbottom, Joseph Pontillo, Yun-Fei Zhu, Warren Wade, John Saunders, Haig Bozigian, R Scott Struthers
Journal of medicinal chemistry · 2008 · doi:10.1021/jm8006454 · PMID:19006286
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This study discovered elagolix, a potent, orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor that suppressed luteinizing hormone in macaques.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 · read from full text ⓘ

This paper reports discovery and pharmacological characterization of elagolix, described as a potent, orally available nonpeptide antagonist of the human gonadotropin-releasing hormone (GnRH) receptor. Antagonist and binding activity were assessed using ligand displacement of radiolabeled GnRH in cells expressing human GnRH receptor (HEK293) and antagonist activity measured by inhibition of GnRH-stimulated inositol phosphate production in RBL1 cells, with Ki values showing sub-nanomolar to low-nanomolar potency in the human system. A stated caveat in the presented data is that potency varies substantially across species and receptor sources (e.g., markedly weaker Ki values for rat GnRH receptor), and CYP3A4 inhibition was also measured as a separate activity with comparatively higher IC50 values. Relevance to endometriosis: GnRH signaling antagonists are discussed/used in the broader context of hormonal modulation for endometriosis in upstream search indexing, though the excerpt provided here contains no explicit endometriosis-specific experiments. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

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-dihydro-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.
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Report error Found 37 Enz. Inhib. hit(s) with all data for entry = 50027623 Affinity DataKi: 0.5nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 0.5nMAssay Description:Antagonist activity at human GnRH receptor expressed in RBL1 cells assessed as inhibition of GnRH-stimulated inositol phosphate productionMore data for this Ligand-Target Pair Affinity DataKi: 0.560nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 0.640nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 0.900nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 1.10nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 1.20nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 1.5nMAssay Description:Antagonist activity at human GnRH receptor expressed in RBL1 cells assessed as inhibition of GnRH-stimulated inositol phosphate productionMore data for this Ligand-Target Pair Affinity DataKi: 2.10nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 2.80nMAssay Description:Antagonist activity at human GnRH receptor expressed in RBL1 cells assessed as inhibition of GnRH-stimulated inositol phosphate productionMore data for this Ligand-Target Pair Affinity DataIC50: 3.20nMAssay Description:Antagonist activity at human GnRH receptor expressed in RBL1 cells assessed as inhibition of GnRH-stimulated inositol phosphate productionMore data for this Ligand-Target Pair TargetGonadotropin-releasing hormone receptor(Rhesus macaque) Neurocrine Biosciences Curated by ChEMBL Neurocrine Biosciences Curated by ChEMBL Affinity DataKi: 3.30nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from monkey GnRH receptor expressed in CHO cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 3.70nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 4.20nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 5.60nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair TargetGonadotropin-releasing hormone receptor(Rhesus macaque) Neurocrine Biosciences Curated by ChEMBL Neurocrine Biosciences Curated by ChEMBL Affinity DataKi: 5.70nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from monkey GnRH receptor expressed in CHO cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 7.60nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 12nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 27nMAssay Description:Antagonist activity at human GnRH receptor expressed in RBL1 cells assessed as inhibition of GnRH-stimulated inositol phosphate productionMore data for this Ligand-Target Pair Affinity DataIC50: 47nMAssay Description:Antagonist activity at human GnRH receptor expressed in RBL1 cells assessed as inhibition of GnRH-stimulated inositol phosphate productionMore data for this Ligand-Target Pair Affinity DataKi: 71nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from human GnRH receptor expressed in HEK293 cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 1.20E+3nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from rat GnRH receptor expressed in CHO cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 4.40E+3nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from rat GnRH receptor expressed in CHO cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: 6.10E+3nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from rat GnRH receptor expressed in CHO cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataKi: >1.00E+4nMAssay Description:Displacement of [125I-Tyr5,DLeu6,NMeLeu7,Pro9-NEt-]GnRH from rat GnRH receptor expressed in CHO cells by liquid scintillation countingMore data for this Ligand-Target Pair Affinity DataIC50: 1.10E+4nMAssay Description:Inhibition of CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 2.90E+4nMAssay Description:Inhibition of CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 3.60E+4nMAssay Description:Inhibition of CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 3.60E+4nMAssay Description:Inhibition of CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 5.60E+4nMAssay Description:Inhibition of CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 6.90E+4nMAssay Description:Inhibition of CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 6.90E+4nMAssay Description:Inhibition of CYP3A4More data for this Ligand-Target Pair Affinity DataIC50: 1.35E+5nMAssay Description:Inhibition of CYP3A4More data for this Ligand-Target Pair

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endometriosis

MeSH descriptors

Drug Discovery Hydrocarbons, Fluorinated Pyrimidines Receptors, LHRH Animals Caco-2 Cells Cytochrome P-450 CYP3A Inhibitors Drug Evaluation, Preclinical Humans Hydrocarbons, Fluorinated Hydrocarbons, Fluorinated Hydrocarbons, Fluorinated Macaca fascicularis Male Microsomes, Liver Microsomes, Liver Microsomes, Liver Molecular Structure Pyrimidines Pyrimidines

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europepmc
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pubmed
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