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

J Med Chem. 2008 Dec 11;51(23):7478-85. doi: 10.1021/jm8006454.


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.

MeSH terms

  • Animals
  • Caco-2 Cells
  • Cytochrome P-450 CYP3A Inhibitors
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Humans
  • Hydrocarbons, Fluorinated / chemistry
  • Hydrocarbons, Fluorinated / metabolism
  • Hydrocarbons, Fluorinated / pharmacology*
  • Macaca fascicularis
  • Male
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Receptors, LHRH / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Time Factors


  • Cytochrome P-450 CYP3A Inhibitors
  • GNRHR protein, human
  • Hydrocarbons, Fluorinated
  • Pyrimidines
  • Receptors, LHRH
  • elagolix