Synthesis and biological evaluation of 3-(2-aminoethyl) uracil derivatives as gonadotropin-releasing hormone (GnRH) receptor antagonists

Eur J Med Chem. 2018 Feb 10;145:413-424. doi: 10.1016/j.ejmech.2017.12.095. Epub 2018 Jan 2.


We investigated a series of uracil analogues by introducing various substituents on the phenyl ring of the N-3 aminoethyl side chain and evaluated their antagonistic activity against human gonadotropin-releasing hormone (GnRH) receptors. Analogues with substituents at the ortho or meta position demonstrated potent in vitro antagonistic activity. Specifically, the introduction of a 2-OMe group enhanced nuclear factor of activated T-cells (NFAT) inhibition up to 6-fold compared to the unsubstituted analogue. We identified compound 12c as a highly potent GnRH antagonist with moderate CYP inhibition. Compound 12c showed potent and prolonged LH suppression after a single dose was orally administered in castrated monkeys compared to a known antagonist, Elagolix. We believe that our SAR study offers useful insights to design GnRH antagonists as a potential treatment option for endometriosis.

Keywords: Endometriosis; GnRH antagonist; Gonadotropin-releasing hormone receptor; Luteinizing hormone.

MeSH terms

  • Animals
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors / administration & dosage
  • Cytochrome P-450 CYP3A Inhibitors / chemistry
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Luteinizing Hormone / antagonists & inhibitors
  • Luteinizing Hormone / blood
  • Macaca fascicularis
  • Molecular Structure
  • Receptors, LHRH / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Uracil / analogs & derivatives
  • Uracil / chemistry
  • Uracil / pharmacology*


  • Cytochrome P-450 CYP3A Inhibitors
  • Receptors, LHRH
  • Uracil
  • Luteinizing Hormone
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human