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

The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(<i>E</i>-oct-4-en-4-yl)-1-phenylamino-2-phenyl-<i>cis</i>-bicyclo[3.3.0]oct-2-ene <b>5</b> 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

Optimized Chemical Probes for REV-ERBα

REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (<b>1</b>) for potency, selectivity, and bioavailability. Potent REV-ERBα agonists <b>4</b>, <b>10</b>, <b>16</b>, and <b>23</b> are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine <b>4</b> demonstrated in vivo bioavailability after either iv or oral dosing

From RORγt Agonist to Two Types of RORγt Inverse Agonists

Biaryl amides as new RORγt modulators were discovered. The crystal structure of biaryl amide agonist <b>6</b> in complex with RORγt ligand binding domain (LBD) was resolved, and both “short” and “long” inverse agonists were obtained by removing from <b>6</b> or adding to <b>6</b> a proper structural moiety. While “short” inverse agonist (<b>8</b>) recruits a corepressor peptide and dispels a coactivator peptide, “long” inverse agonist (<b>9</b>) dispels both. The two types of inverse agonists can be utilized as potential tools to study mechanisms of Th17 transcriptional network inhibition and related disease biology

Discovery of Tertiary Amine and Indole Derivatives as Potent RORγt Inverse Agonists

A novel series of tertiary amines as retinoid-related orphan receptor gamma-t (RORγt) inverse agonists was discovered through agonist/inverse agonist conversion. The level of RORγt inhibition can be enhanced by modulating the conformational disruption of H12 in RORγt LBD. Linker exploration and rational design led to the discovery of more potent indole-based RORγt inverse agonists