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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.

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				R. S. Struthers, A. J. Nicholls, J. Grundy, T. Chen, R. Jimenez, S. S. C. Yen, and H. P. Bozigian Suppression of Gonadotropins and Estradiol in Premenopausal Women by Oral Administration of the Nonpeptide Gonadotropin-Releasing Hormone Antagonist Elagolix J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 545 - 551. [Abstract] [Full Text] [PDF]