Download MendeleySmall Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2).
Whitby, R.J., Stec, J., Blind, R.D., Dixon, S., Leesnitzer, L.M., Orband-Miller, L.A., Williams, S.P., Willson, T.M., Xu, R., Zuercher, W.J., Cai, F., Ingraham, H.A.(2011) J Med Chem 54: 2266-2281
- PubMed: 21391689
- DOI: https://doi.org/10.1021/jm1014296
- Primary Citation of Related Structures:
3PLZ - PubMed Abstract:
The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.
Organizational Affiliation:
School of Chemistry, University of Southampton, Southampton, Hants, SO17 1BJ, United Kingdom. [email protected]
