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-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.
Chen
Chen
C
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA. cchen@neurocrine.com
Wu
Dongpei
D
Guo
Zhiqiang
Z
Xie
Qiu
Q
Reinhart
Greg J
GJ
Madan
Ajay
A
Wen
Jenny
J
Chen
Takung
T
Huang
Charles Q
CQ
Chen
Mi
M
Chen
Yongsheng
Y
Tucci
Fabio C
FC
Rowbottom
Martin
M
Pontillo
Joseph
J
Zhu
Yun-Fei
YF
Wade
Warren
W
Saunders
John
J
Bozigian
Haig
H
Struthers
R Scott
RS
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
D065692:Cytochrome P-450 CYP3A Inhibitors; C484844:GNRHR protein, human; D006845:Hydrocarbons, Fluorinated; D011743:Pyrimidines; D011966:Receptors, LHRH; C539351:elagolix