Abstract

. The applicant proposes to develop a non-peptide, orally active GnRH antagonist that may useful in the treatment of diseases such as prostate cancer, breast cancer, endometriosis and uterine fibroids. The applicant will employ high-throughput parallel synthesis of defined combinatorial chemical libraries based upon three selected small molecule frameworks discovered in the screening of in-house chemical libraries and rational design. The potency of the synthesized molecules will be determined by membrane-binding assays using a cell line that expresses the cloned human GnRH receptor. The applicant will also develop a panel of mutant GnRH receptors and receptors from several species to determine the receptor contact sites through profiling of the small molecule libraries. This will allow the applicant to pool information from multiple ligand families based upon knowledge of common receptor interactions.
The specific aims, proposed in Phase I, are designed to generate potent GnRH antagonists together with the data necessary to develop them into valid clinical candidates in Phase II.

Proposed Commercial Applications

NOT AVAILABLE

  Funding Agency

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 I (R43)
Project #
1R43HD038625-01
Application #
6073967
Study Section
Special Emphasis Panel (ZRG1-REN (02))
Program Officer
De Paolo, Louis V
Project Start
2000-04-05
Project End
2000-10-04
Budget Start
2000-04-05
Budget End
2000-10-04
Support Year
1
Fiscal Year
2000
Total Cost
$99,931
Indirect Cost

  Institution

Name
Neurocrine Biosciences, Inc.
Department
Type
DUNS #
800981276
City
San Diego
State
CA
Country
United States
Zip Code
92130

  Publications

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; 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
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
Zhu, Yun-Fei; Guo, Zhiqiang; Gross, Timothy D et al. (2003) Design and structure-activity relationships of 2-alkyl-3-aminomethyl-6-(3-methoxyphenyl)-7-methyl-8-(2-fluorobenzyl)imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists. J Med Chem 46:1769-72
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

Showing the most recent 10 out of 13 publications