Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902.
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.
Struthers
R Scott
RS
Department of Endocrinology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130, USA. sstruthers@neurocrine.com
Xie
Qui
Q
Sullivan
Susan K
SK
Reinhart
Greg J
GJ
Kohout
Trudy A
TA
Zhu
Yun-Fei
YF
Chen
Chen
C
Liu
Xin-Jun
XJ
Ling
Nicholas
N
Yang
Weidong
W
Maki
Richard A
RA
Bonneville
Anne K
AK
Chen
Ta-Kung
TK
Bozigian
Haig P
HP
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
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