title: Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902.
abstract: Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the 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 after oral administration. Here we report the in vitro and in vivo pharmacological 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 IP accumulation, Ca(2+) 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 after oral administration. Overall, these data provide a benchmark of pharmacological 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.
authors.affiliation: Department of Endocrinology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130, USA. sstruthers@neurocrine.com
authors.forename: R Scott
authors.initials: RS
authors.lastname: Struthers
authors.forename: Qui
authors.initials: Q
authors.lastname: Xie
authors.forename: Susan K
authors.initials: SK
authors.lastname: Sullivan
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Reinhart
authors.forename: Trudy A
authors.initials: TA
authors.lastname: Kohout
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Zhu
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Xin-Jun
authors.initials: XJ
authors.lastname: Liu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ling
authors.forename: Weidong
authors.initials: W
authors.lastname: Yang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Maki
authors.forename: Anne K
authors.initials: AK
authors.lastname: Bonneville
authors.forename: Ta-Kung
authors.initials: TK
authors.lastname: Chen
authors.forename: Haig P
authors.initials: HP
authors.lastname: Bozigian
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D007986:Luteinizing Hormone / Q000097:blood; D008251:Macaca; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009919:Orchiectomy; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013941:Thymine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C498569:3-(2-amino-2-phenylethyl)-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione; D002121:Calcium Channel Blockers; D007295:Inositol Phosphates; D008024:Ligands; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013941:Thymine