Identification of Small Molecule Agonists of the Orphan Nuclear Receptors Liver Receptor Homolog-1 and Steroidogenic Factor-1
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- 作者：Richard J. Whitby ; Sally Dixon ; Patrick R. Maloney ; Philippe Delerive ; Bryan J. Goodwin ; Derek J. Parks ; Timothy M. Willson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：November 16, 2006
- 年：2006
- 卷：49
- 期：23
- 页码：6652 - 6655
- 全文大小：49K
- 年卷期：v.49,no.23(November 16, 2006)
- ISSN：1520-4804
文摘
We report the identification of substituted cis-bicyclo[3.3.0]oct-2-enes as small molecule agonists of subfamily V orphan nuclearreceptors (NR5A), liver receptor homolog-1 (LRH-1) and steroidogenicfactor-1 (SF-1). Using fluorescence resonance energy transfer (FRET)-based biochemical assays, compound 5a (GSK8470) was identified asa high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increasedthe expression of the LRH-1 target gene small heterodimer partner(SHP). Synthesis of analogues modified at three positions led to thedevelopment of compounds with functional selectivity between LRH-1and SF-1.