Identification of small molecule agonists of the orphan nuclear receptors liver receptor homolog-1 and steroidogenic factor-1.
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.
Whitby
Richard J
RJ
School of Chemistry, University of Southampton, Southampton, HANTS, SO17 1BJ, UK.
Dixon
Sally
S
Maloney
Patrick R
PR
Delerive
Philippe
P
Goodwin
Bryan J
BJ
Parks
Derek J
DJ
Willson
Timothy M
TM
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000819:agonists*; D031541:Fluorescence Resonance Energy Transfer; D017930:Genes, Reporter; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000819:agonists*; D006801:Humans; D008024:Ligands; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D013237:Stereoisomerism; D054339:Steroidogenic Factor 1; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists*
D000475:Alkenes; D000814:Aniline Compounds; D001643:Bridged Bicyclo Compounds; D004268:DNA-Binding Proteins; C516216:GSK 8470; D018398:Homeodomain Proteins; D008024:Ligands; C515057:NR5A1 protein, human; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2