NOVEL NON-PEPTIDE ANTAGONIST OF THE GNRH RECEPTOR

GNRH 受体的新型非肽拮抗剂

• 批准号: 6073967
• 负责人: RICHARD SCOTT STRUTHERS
• 金额: $ 9.99万
• 依托单位: NEUROCRINE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-05 至 2000-10-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6073967
• 关键词: breast neoplasms; cell line; chemical registry /resource; combinatorial chemistry; drug design /synthesis /production; drug screening /evaluation; endometriosis; gonadotropin releasing factor; hormone inhibitor; hormone receptor; molecular cloning; oral administration; prostate neoplasms; receptor expression

DESCRIPTION: (adapted from the applicant's 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 APPLICATION: NOT AVAILABLE

描述：（改编自申请人的摘要）。申请人提议 开发一种非肽、口服活性 GnRH 拮抗剂，可用于 治疗前列腺癌、乳腺癌、子宫内膜异位症等疾病 子宫肌瘤。申请人将采用高通量并行合成 基于三个选定的小化合物定义的组合化学库 在内部化学库筛选中发现的分子框架 和合理的设计。合成分子的效力为 使用表达的细胞系通过膜结合测定来确定 克隆人 GnRH 受体。申请人还将开发一组突变体 GnRH受体和从几个物种的受体中确定的受体 通过小分子库的分析来确定接触位点。这将 允许申请人汇集来自多个配体家族的信息 基于常见受体相互作用的知识。中提出的具体目标 I 期旨在与 GnRH 拮抗剂一起产生有效的 GnRH 拮抗剂 将它们开发为第二阶段有效临床候选者所需的数据。 拟议的商业应用：不可用

项目成果

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.

促性腺激素释放激素受体的非肽拮抗剂的物种选择性由细胞外环II和III以及氨基末端中的残基决定。

• 发表时间: 2004-08-13
• 作者: Reinhart, Greg J;Xie, Qiu;Liu, Xin;Zhu, Yun;Fan, Jun;Chen, Chen;Struthers, R Scott
• 通讯作者: Struthers, R Scott

Suppression of serum luteinizing hormone in postmenopausal women by an orally administered nonpeptide antagonist of the gonadotropin-releasing hormone receptor (NBI-42902).

通过口服促性腺激素释放激素受体非肽拮抗剂 (NBI-42902) 抑制绝经后妇女的血清黄体生成激素。

• 发表时间: 2006-10
• 作者: Struthers, R Scott;Chen, TaKung;Campbell, Bruce;Jimenez, Roland;Pan, Henry;Yen, Samuel S C;Bozigian, Haig P
• 通讯作者: Bozigian, Haig P

Synthesis and initial structure-activity relationships of a novel series of imidazolo[1,2-a]pyrimid-5-ones as potent GnRH receptor antagonists.

作为有效 GnRH 受体拮抗剂的一系列新型咪唑并[1,2-a]嘧啶-5-酮的合成和初始构效关系。

• 发表时间: 2002-08-19
• 影响因子: 2.7
• 作者: Wilcoxen, Keith M;Zhu, Yun Fei;Connors, Patrick J;Saunders, John;Gross, Timothy D;Gao, Yinghong;Reinhart, Greg J;Struthers, R Scott;Chen, Chen
• 通讯作者: Chen, Chen

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.

尿嘧啶衍生的人 GnRH 受体拮抗剂的合成和构效关系：含有取代的噻吩或噻唑的 (R)-3-[2-(2-氨基)苯乙基]-1-(2,6-二氟苄基)-6-甲基尿嘧啶

• 发表时间: 2004-10-04
• 作者: Rowbottom, Martin W;Tucci, Fabio C;Connors Jr, Patrick J;Gross, Timothy D;Zhu, Yun;Guo, Zhiqiang;Moorjani, Manisha;Acevedo, Oscar;Carter, Lee;Sullivan, Susan K;Xie, Qiu;Fisher, Andrew;Struthers, R Scott;Saunders, John;Chen, Chen
• 通讯作者: Chen, Chen

Identification of 1-arylmethyl-3- (2-aminoethyl)-5-aryluracil as novel gonadotropin-releasing hormone receptor antagonists.

鉴定 1-芳基甲基-3-(2-氨基乙基)-5-芳基尿嘧啶作为新型促性腺激素释放激素受体拮抗剂。

• 发表时间: 2003-05-22
• 作者: Zhu, Yun;Gross, Timothy D;Guo, Zhiqiang;Connors Jr, Patrick J;Gao, Yinghong;Tucci, Fabio C;Struthers, R Scott;Reinhart, Greg J;Saunders, John;Chen, Ta Kung;Killam Bonneville, Anne L;Chen, Chen
• 通讯作者: Chen, Chen