NOVEL NON-PEPTIDE ANTAGONIST OF THE GNRH RECEPTOR

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

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