Efficacy of selective RAR-related orphan receptor gamma (RORγ) inverse agonists in psoriasis and asthma models (CCR6P.278)
2014
Th17 cells play a key pro-inflammatory role in a variety of autoimmune diseases. The nuclear hormone receptor RORγ controls the differentiation of Th17 cells and expression of IL-17. RORγ inverse agonists were designed using a combination of approaches including structure and knowledge based methods. Compounds were screened in a RORγ radio-ligand binding assay using 3H 25-Hydroxycholesterol, as well as in a cell based reporter assay to demonstrate inverse agonism. Compounds from multiple structural classes have been identified, with IC50 in the range of 5 - 500 nM in binding assay. Co-crystal structures of RORγ in complex with known as well as in-house compounds were utilized to optimize the lead compounds. Compounds from the lead series demonstrated good activity ( 10 fold selectivity against RORα as well as other nuclear receptors. Compounds from multiple series have shown significant inhibition of IL-17 release from differentiated mouse and human Th17 cells. Lead compounds have shown good pharmacokinetic properties in mice. Efficacy of lead compounds have been demonstrated in IMQ induced Psoriasis model as well as in intranasal OVA/LPS induced asthma model. In summary, we have identified structurally diverse small molecule inverse agonists of RORγ and have demonstrated efficacy in Th17 mediated efficacy models.
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