Identification of Small Molecule Agonists of the Orphan Nuclear Receptors Liver Receptor Homolog-1 and Steroidogenic Factor-1
Journal of Medicinal Chemistry2006Vol. 49(23), pp. 6652–6655
Citations Over TimeTop 14% of 2006 papers
Richard J. Whitby, Sally Dixon, Patrick Maloney, Philippe Delerive, Bryan Goodwin, Derek J. Parks, Timothy M. Willson
Abstract
We report the identification of substituted cis-bicyclo[3.3.0]-oct-2-enes as small molecule agonists of subfamily V orphan nuclear receptors (NR5A), liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). Using fluorescence resonance energy transfer (FRET)-based biochemical assays, compound 5a (GSK8470) was identified as a high-affinity ligand for LRH-1 and SF-1. In liver cells, 5a increased the expression of the LRH-1 target gene small heterodimer partner (SHP). Synthesis of analogues modified at three positions led to the development of compounds with functional selectivity between LRH-1 and SF-1.
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