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NBI-42902

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. see: R. Scott Struthers et al: Pharmacological Characterization of a Novel Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor, NBI-42902. Endocrinology Vol. 148, No. 2 857-867

 Current developer:   Neurocrine Biosciences, Inc

 1: Sullivan SK, Brown MS, Gao Y, Loweth CJ, Lio FM, Crowe PD, Struthers RS, Betz SF. Allosteric and orthosteric binding modes of two nonpeptide human gonadotropin-releasing hormone receptor antagonists. Biochemistry. 2006 Dec 26;45(51):15327-37. Epub 2006 Dec 1. PubMed PMID: 17176055.

2: Struthers RS, Xie Q, Sullivan SK, Reinhart GJ, Kohout TA, Zhu YF, Chen C, Liu XJ, Ling N, Yang W, Maki RA, Bonneville AK, Chen TK, Bozigian HP. Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902. Endocrinology. 2007 Feb;148(2):857-67. Epub 2006 Nov 9. PubMed PMID: 17095587.

3: Sullivan SK, Hoare SR, Fleck BA, Zhu YF, Heise CE, Struthers RS, Crowe PD. Kinetics of nonpeptide antagonist binding to the human gonadotropin-releasing hormone receptor: Implications for structure-activity relationships and insurmountable antagonism. Biochem Pharmacol. 2006 Sep 28;72(7):838-49. Epub 2006 Aug 22. PubMed PMID: 16930559.

4: Struthers RS, Chen T, Campbell B, Jimenez R, Pan H, Yen SS, Bozigian HP. Suppression of serum luteinizing hormone in postmenopausal women by an orally administered nonpeptide antagonist of the gonadotropin-releasing hormone receptor (NBI-42902). J Clin Endocrinol Metab. 2006 Oct;91(10):3903-7. Epub 2006 Jul 18. PubMed PMID: 16849403.

5: Ayabe T. [An outline of GnRH analogue]. Nippon Rinsho. 2006 Apr;64 Suppl 4:64-9. Review. Japanese. PubMed PMID: 16689286.

6: Betz SF, Reinhart GJ, Lio FM, Chen C, Struthers RS. Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor. J Med Chem. 2006 Jan 26;49(2):637-47. PubMed PMID: 16420049.

7: Tucci FC, Hu T, Mesleh MF, Bokser A, Allsopp E, Gross TD, Guo Z, Zhu YF, Struthers RS, Ling N, Chen C. Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6- methyluracil. Chirality. 2005 Nov;17(9):559-64. PubMed PMID: 16196024.

8: Tucci FC, Zhu YF, Struthers RS, Guo Z, Gross TD, Rowbottom MW, Acevedo O, Gao Y, Saunders J, Xie Q, Reinhart GJ, Liu XJ, Ling N, Bonneville AK, Chen T, Bozigian H, Chen C. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization. J Med Chem. 2005 Feb 24;48(4):1169-78. PubMed PMID: 15715483.