Novel Non-Peptide Antagonists of the GnRH Receptor

描述（由申请人提供）：前列腺癌，乳腺癌， 子宫内膜异位症和子宫肌瘤是相当常见和严重的疾病， 男人和女人他们的病因尚未完全了解，但都可以治疗 通过去除内源性性腺类固醇激素、睾酮和雌激素。 这导致了几种成功的药物产品的发现 基于阻断下丘脑肽的作用， 促性腺激素释放激素（GnRH）。GnRH受体的下调 肽超激动剂或肽拮抗剂阻断， 促性腺激素分泌，并导致性腺类固醇激素急剧减少 生产基于GnRH的药物现在广泛用于这些患者， 以及作为辅助生殖治疗的一部分的激素操纵， 治疗性早熟在这里，我们建议开发口服活性 GnRH受体的小分子拮抗剂，以克服许多 这些可注射肽类药物的局限性，并扩大了临床 基于GnRH的策略的效用。在第一阶段，我们使用了高通量 平行有机合成设计多个化学系列的高效， 非肽类GnRH拮抗剂。我们还建立了一系列体外和 体内测定以评价这些化合物的吸收、分布和代谢 化合物.在第二阶段，我们提出了一个平行合成化学的组合， 以及优化药代动力学和药效学特性的测定策略 从这些系列中的三个系列的化合物中分离， 用于临床开发。 拟议商业应用：不可用

DESCRIPTION (provided by applicant): Prostate cancer, breast cancer, endometriosis and uterine fibroids are fairly common and serious diseases in men and women. Their etiology is not fully understood, but all can be treated by removal of endogenous gonadal steroid hormones, testosterone and estrogen. This has led to the discovery of several successful pharmaceutical products based on blocking the actions of the hypothalamic peptide, gonadotropin-releasing hormone (GnRH). Down-regulation of the GnRH receptor by peptide superagonists, or blockade by peptide antagonists, prevents pituitary gonadotropin secretion and leads to dramatic reductions in gonadal steroid production. GnRH-based drugs are now used extensively in these patients, as well as for hormonal manipulation as part of assisted reproductive therapy or for treatment of precocious puberty. Here we propose to develop orally active small molecule antagonists of the GnRH receptor, in order to overcome many of the limitations of these injectable peptide drugs and expand the clinical utility of GnRH-based strategies. In Phase I we have used high-throughput parallel organic synthesis to design multiple chemical series of highly potent, nonpeptide GnRH antagonists. We have also established a series of in vitro and in vivo assays to evaluate absorption, distribution and metabolism of these compounds. In Phase II we propose a combination of parallel synthetic chemistry and assay strategies to optimize pharmacokinetic and pharmacodynamic properties of compounds from three of these series in order to produce compounds suitable for clinical development. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE