This Article Full Text Full Text (PDF) All Versions of this Article: 148/2/857    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Struthers, R. S. Articles by Bozigian, H. P. Search for Related Content PubMed PubMed Citation Articles by Struthers, R. S. Articles by Bozigian, H. P.

Pharmacological Characterization of a Novel Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor, NBI-42902

Departments of Endocrinology (R.S.S., X.-J.L., Q.X., G.J.R., T.A.K.), Pharmacology (S.K.S.), Medicinal Chemistry (Y.-F.Z., C.C.), Peptide Chemistry (N.L.), Molecular Biology (W.Y., R.A.M.), and Preclinical Development (A.K.B., T.-K.C., H.P.B.), Neurocrine Biosciences Inc., San Diego, California 92130

Address all correspondence and requests for reprints to: Dr. R. Scott Struthers, Department of Endocrinology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130. E-mail: sstruthers{at}neurocrine.com.

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, 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 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.