NOVEL NON-PEPTIDE ANTAGONIST OF THE GNRH RECEPTOR

描述：（改编自申请人的摘要）。申请人建议 开发一种非肽类口服活性GnRH拮抗剂， 治疗疾病如前列腺癌、乳腺癌、子宫内膜异位症和 子宫肌瘤申请人将采用高通量平行合成 基于三个选择的小的确定的组合化学库， 在筛选内部化学文库中发现的分子框架 合理的设计。合成分子的效力将是 通过使用表达该蛋白的细胞系的膜结合测定来确定。 克隆的人GnRH受体。申请人还将开发一组突变体 GnRH受体和来自几个物种的受体，以确定受体 通过小分子文库的特征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， 基于对共同受体相互作用的了解。具体目标，在 I期，旨在产生有效的GnRH拮抗剂与 将其开发为II期有效临床候选药物所需的数据。 拟议商业应用：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