NOVEL NON-PEPTIDE ANTAGONIST OF THE GNRH RECEPTOR

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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