Novel Drug Target for Bile and Cholesterol Metabolism

描述（由申请人提供）：调节胆汁酸代谢是治疗高胆固醇血症和胆汁淤积的治疗靶点。直接调节肝胆汁形成和运输的治疗选择是有限的。Orphagen计划开发并商业化通过孤儿核受体LRH-1（肝脏受体同源物-1）调节基因转录的铅分子。LRH-1似乎刺激逆向胆固醇运输、胆汁形成和胆汁运输。鉴定首批对LRH-1具有药理活性的化合物的努力是一个更大项目的一部分，该项目旨在为调节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I期研究中，LRH-1化合物筛选的间接结合试验将基于dr。霍莉·英格拉姆和基普·盖伊在加州大学旧金山分校。LRH-1将针对Orphagen公司开发的小分子化合物库进行筛选。基于细胞的报告基因检测将并行实施，以加速鉴定和确认调节LRH-1基因转录的小分子。适合高胆固醇血症和胆汁淤积症动物研究的候选药物将在II期合成和测试，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.