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.
Chen Chen  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA. [email protected]
PMID: 19006286 DOI: 10.1021/jm8006454
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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