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SW1353 cells represent a useful human cell model as they conserve many Sox9 signaling pathways previously demonstrated in mouse chondrocytes. We identify FGF-9 as a particularly potent Sox9 agonist. The antagonism between FGFs and cytokines on Sox9 expression and Col2 enhancer activity suggests that Sox9 integrates the opposing activities of FGFs and cytokines. We also find that SW1353 cells respond to very low doses of IL-1 with Col2 enhancer activation, while increasing doses lead to repression.

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As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.

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