Prostate cancer, breast cancer, endometriosis and uterine fibroids are fairly common and serious diseases in men and women. Their etiology is not fully understood, but all can be treated by removal of endogenous gonadal steroid hormones, testosterone and estrogen. This has led to the discovery of several successful pharmaceutical products based on blocking the actions of the hypothalamic peptide, gonadotropin-releasing hormone (GnRH). Down-regulation of the GnRH receptor by peptide superagonists, or blockade by peptide antagonists, prevents pituitary gonadotropin secretion and leads to dramatic reductions in gonadal steroid production. GnRH-based drugs are now used extensively in these patients, as well as for hormonal manipulation as part of assisted reproductive therapy or for treatment of precocious puberty. Here we propose to develop orally active small molecule antagonists of the GnRH receptor, in order to overcome many of the limitations of these injectable peptide drugs and expand the clinical utility of GnRH-based strategies. In Phase I we have used high-throughput parallel organic synthesis to design multiple chemical series of highly potent, nonpeptide GnRH antagonists. We have also established a series of in vitro and in vivo assays to evaluate absorption, distribution and metabolism of these compounds. In Phase II we propose a combination of parallel synthetic chemistry and assay strategies to optimize pharmacokinetic and pharmacodynamic properties of compounds from three of these series in order to produce compounds suitable for clinical development.

Proposed Commercial Applications

NOT AVAILABLE

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44HD038625-03
Application #
6526374
Study Section
Special Emphasis Panel (ZRG1-BCE (10))
Program Officer
De Paolo, Louis V
Project Start
2000-04-05
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$471,580
Indirect Cost
Name
Neurocrine Biosciences, Inc.
Department
Type
DUNS #
800981276
City
San Diego
State
CA
Country
United States
Zip Code
92130
Struthers, R Scott; Nicholls, Andrew J; Grundy, John et al. (2009) Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix. J Clin Endocrinol Metab 94:545-51
Struthers, R Scott; Xie, Qui; Sullivan, Susan K et al. (2007) Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902. Endocrinology 148:857-67
Struthers, R Scott; Chen, TaKung; Campbell, Bruce et al. (2006) 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 91:3903-7
Guo, Zhiqiang; Chen, Yongsheng; Huang, Charles Q et al. (2005) Uracils as potent antagonists of the human gonadotropin-releasing hormone receptor without atropisomers. Bioorg Med Chem Lett 15:2519-22
Rowbottom, Martin W; Tucci, Fabio C; Connors Jr, Patrick J et al. (2004) Synthesis and structure-activity relationships of uracil derived human GnRH receptor antagonists: (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5. Bioorg Med Chem Lett 14:4967-73
Tucci, Fabio C; Zhu, Yun-Fei; Guo, Zhiqiang et al. (2004) 3-(2-aminoalkyl)-1-(2,6-difluorobenzyl)-5- (2-fluoro-3-methoxyphenyl)-6-methyl-uracils as orally bioavailable antagonists of the human gonadotropin releasing hormone receptor. J Med Chem 47:3483-6
Rowbottom, Martin W; Tucci, Fabio C; Zhu, Yun-Fei et al. (2004) Synthesis and structure-activity relationships of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils as human GnRH receptor antagonists. Bioorg Med Chem Lett 14:2269-74
Reinhart, Greg J; Xie, Qiu; Liu, Xin-Jun et al. (2004) Species selectivity of nonpeptide antagonists of the gonadotropin-releasing hormone receptor is determined by residues in extracellular loops II and III and the amino terminus. J Biol Chem 279:34115-22
Zhu, Yun-Fei; Gross, Timothy D; Guo, Zhiqiang et al. (2003) Identification of 1-arylmethyl-3- (2-aminoethyl)-5-aryluracil as novel gonadotropin-releasing hormone receptor antagonists. J Med Chem 46:2023-6
Tucci, Fabio C; Zhu, Yun-Fei; Guo, Zhiqiang et al. (2003) Synthesis and structure-activity relationships of 1-arylmethyl-3-(1-methyl-2-amino)ethyl-5-aryl-6-methyluracils as antagonists of the human GnRH Receptor. Bioorg Med Chem Lett 13:3317-22

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