Novel Drug Target for Bile and Cholesterol Metabolism

描述(申请人提供)：调节胆汁酸代谢是治疗高胆固醇血症和胆汁淤积的治疗目标，胆汁淤积是胆汁在肝脏中的病理性堆积。直接调节肝脏胆汁形成和转运的治疗选择有限。奥菲根建议开发通过孤儿核受体LRH-1(肝脏受体同源1)调节基因转录的铅分子并将其商业化。LRH-1似乎可以刺激胆固醇的反向转运、胆汁的形成和胆汁的转运。寻找第一个对LRH-1具有药理活性的化合物的努力，是一个更大的项目的一部分，该项目旨在为调控哺乳动物类固醇和胆固醇代谢的结构相关的孤儿核受体创造药物。在第一阶段，将根据加州大学旧金山分校的Holly Ingraham和Kip Guy博士的研究结果，在LRH-1实施化合物筛选的间接结合分析。LRH-1将与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分析将并行实施，以加速识别和确认由LRH-1调控基因转录的小分子。适用于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，并招募一个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.