Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the gonadotropin-releasing hormone (GnRH) receptor has found widespread use in clinical practice for the management of sex steroid dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902 that suppresses serum LH concentrations in postmenopausal women following oral administration. Here we report the in vitro and in vivo pharmacologic characterization of this compound. NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor (K_i = 0.56 nM). Tritiated NBI-42902 binds with high affinity (K_d = 0.19 nM) to a single class of binding sites and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH stimulated inositol phosphate accumulation, Ca²⁺ flux, and ERK1/2 activation. It did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques following oral administration. Overall, these data provide a benchmark of pharmacologic characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis.