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.
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