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)。申请人建议： 开发一种非肽、口服活性的GnRH拮抗剂，该药可能在 前列腺癌、乳腺癌、子宫内膜异位症等疾病的治疗 子宫肌瘤。申请者将采用高通量并行合成 基于三个选定的小的已定义组合化学库 在筛选内部化学文库中发现的分子框架 合理的设计。合成的分子的效力将是 通过使用表达该基因的细胞系的膜结合试验来确定 克隆人促性腺激素释放激素受体。申请者还将开发一种突变型 促性腺激素释放激素受体和几种受体的测定 通过小分子文库的图谱分析联系位点。这将是 允许申请者汇集来自基于多个配体家族的信息 基于对常见受体相互作用的了解。年提出的具体目标 第一阶段，旨在产生有效的GnRH拮抗剂与 在第二阶段将他们发展为有效的临床候选者所需的数据。 建议的商业应用：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。

• DOI: 10.1074/jbc.m404474200
• 发表时间: 2004
• 期刊: The Journal of biological chemistry
• 作者: Reinhart,GregJ;Xie,Qiu;Liu,Xin-Jun;Zhu,Yun-Fei;Fan,Jun;Chen,Chen;Struthers,RScott
• 通讯作者: Struthers,RScott

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.

• DOI: 10.1016/s0960-894x(03)00619-x
• 发表时间: 2003-10
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: F. Tucci;Yun-fei Zhu;Zhiqian Guo;T. Gross;Patrick J. Connors;R. Struthers;Greg J. Reinhart;J. Saunders-J.

A novel synthesis of 7-aryl-8-fluoro-pyrrolo[1,2-a]pyrimid-4-ones as potent, stable GnRH receptor antagonists.

• DOI: 10.1016/s0960-894x(02)00745-x
• 发表时间: 2002-12
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: F. Tucci;Yun-fei Zhu;Zhiqian Guo;T. Gross;Patrick J. Connors;R. Struthers;Greg J. Reinhart;Xiaochuan Wang;J. Saunders;Chen 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。

• DOI: 10.1021/jm034041s
• 发表时间: 2003
• 期刊: Journal of medicinal chemistry.
• 作者: Zhu,Yun-Fei;Gross,TimothyD;Guo,Zhiqiang;ConnorsJr,PatrickJ;Gao,Yinghong;Tucci,FabioC;Struthers,RScott;Reinhart,GregJ;Saunders,John;Chen,TaKung;KillamBonneville,AnneL;Chen,Chen
• 通讯作者: Chen,Chen

Synthesis and structure-activity relationships of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils as human GnRH receptor antagonists.

作为人 GnRH 受体拮抗剂的 (R)-1-烷基-3-[2-(2-氨基)苯乙基]-5-(2-氟苯基)-6-甲基尿嘧啶的合成和构效关系。

• DOI: 10.1016/j.bmcl.2004.02.004
• 发表时间: 2004
• 期刊: Bioorganic & medicinal chemistry letters.
• 作者: Rowbottom,MartinW;Tucci,FabioC;Zhu,Yun-Fei;Guo,Zhiqiang;Gross,TimothyD;Reinhart,GregJ;Xie,Qui;Struthers,RScott;Saunders,John;Chen,Chen
• 通讯作者: Chen,Chen