Novel Drug Target for Bile and Cholesterol Metabolism

描述（由申请方提供）：胆汁酸代谢的调节是治疗高胆固醇血症以及胆汁淤积（胆汁在肝脏中的病理性积聚）的治疗靶点。直接调节肝胆汁形成和转运的治疗选择有限。Orphagen提出开发和商业化通过孤儿核受体LRH-1（肝脏受体同系物-1）调节基因转录的先导分子。LRH-1似乎刺激胆固醇逆向转运、胆汁形成和胆汁转运。鉴定LRH-1的第一个活性化合物的努力是一个更大计划的一部分，该计划旨在为调节哺乳动物类固醇和胆固醇代谢的结构相关孤儿核受体创造药物。在I期，将根据U. S.冬青英格拉哈姆和Kip Guy博士的发现，在LRH-1进行化合物筛选的间接结合试验。C.旧金山弗朗西斯科。LRH-1将针对在Orphagen开发的聚焦小分子化合物文库进行筛选。基于细胞的报告基因测定将平行实施，以加速鉴定和确认LRH-1调节基因转录的小分子。适合高胆固醇血症和胆汁淤积动物研究的候选药物将在第二阶段合成和测试，并招募战略合作伙伴进行进一步开发。

DESCRIPTION (provided by applicant): Regulation of bile acid metabolism is a therapeutic target for treatment of hypercholesterolemia as well as for cholestasis, the pathological buildup of bile in liver. Therapeutic options for direct modulation of hepatic bile formation and transport are limited. Orphagen proposes to develop and commercialize lead molecules that regulate gene transcription by the orphan nuclear receptor LRH-1 (liver receptor homolog-1). LRH-1 appears to stimulate reverse cholesterol transport, bile formation, and bile transport. The effort to identify the first pharmacologically active compounds to LRH-1 is part of a larger program to create drugs to structurally-related orphan nuclear receptors that regulate mammalian steroid and cholesterol metabolism. In Phase I, an indirect binding assay for compound screening at LRH-1 will be implemented based on findings from Drs. Holly Ingraham and Kip Guy at U. C. San Francisco. LRH-1 will be screened against a focused small molecule compound library developed at Orphagen. Cell-based reporter gene assays will be implemented in parallel to accelerate identification and confirmation of small molecules that regulate gene transcription by LRH-1. Drug candidates suitable for animal studies of hypercholesterolemia and cholestasis will be synthesized and tested in Phase II and a strategic partner recruited for further development.