Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2)

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, RJW103). The series based on 1-ethenyl substitution were acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.

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Identifiers

ORCID for Richard J. Whitby: orcid.org/0000-0002-9891-5502

ORCID for Sally Dixon: orcid.org/0000-0003-2219-3635

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