Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

• Published in: Journal of medicinal chemistry Vol. 54; no. 7; pp. 2266 - 2281
• Main Authors: Whitby, Richard J, Stec, Jozef, Blind, Raymond D, Dixon, Sally, Leesnitzer, Lisa M, Orband-Miller, Lisa A, Williams, Shawn P, Willson, Timothy M, Xu, Robert, Zuercher, William J, Cai, Fang, Ingraham, Holly A
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.04.2011; Amer Chemical Soc
• Subjects: 60 APPLIED LIFE SCIENCES; Amino Acid Sequence; ANIMAL CELLS; Animals; BASIC BIOLOGICAL SCIENCES; Chemistry, Medicinal; CRYSTAL STRUCTURE; Crystallography, X-Ray; GENES; HEK293 Cells; Humans; Life Sciences & Biomedicine; Ligands; LIVER; Mice; Models, Molecular; Molecular Sequence Data; PEPTIDES; Pharmacology & Pharmacy; Protein Conformation; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - metabolism; REGULATIONS; Science & Technology; Sequence Homology, Amino Acid; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Steroidogenic Factor 1 - agonists; Steroidogenic Factor 1 - chemistry; Steroidogenic Factor 1 - metabolism; TARGETS; Transcriptional Activation - drug effects; BREAST-CANCER; TARGET; ACTIVATES SF-1; DRUG DISCOVERY; PROMOTER-II; CELL-PROLIFERATION; SYSTEM-SPECIFIC KNOCKOUT; COUPLING-CONSTANTS; ESTROGEN-RECEPTOR; AROMATASE EXPRESSION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1014296

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.