title: 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.
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.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA. cchen@neurocrine.com
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Dongpei
authors.initials: D
authors.lastname: Wu
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Guo
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xie
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Reinhart
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Takung
authors.initials: T
authors.lastname: Chen
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Huang
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chen
authors.forename: Fabio C
authors.initials: FC
authors.lastname: Tucci
authors.forename: Martin
authors.initials: M
authors.lastname: Rowbottom
authors.forename: Joseph
authors.initials: J
authors.lastname: Pontillo
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Warren
authors.initials: W
authors.lastname: Wade
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Haig
authors.initials: H
authors.lastname: Bozigian
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D065692:Cytochrome P-450 CYP3A Inhibitors; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; C484844:GNRHR protein, human; D006845:Hydrocarbons, Fluorinated; D011743:Pyrimidines; D011966:Receptors, LHRH; C539351:elagolix