Discovery of selective RORγ inverse agonists and demonstration of efficacy in inflammatory disease models

The nuclear hormone receptor RORγ controls the differentiation of Th17 cells that plays a key pro-inflammatory role in a variety of autoimmune diseases. RORγ inverse agonists from multiple structural classes were discovered and screened in a RORγ radio-ligand binding assay as well as in a cell based reporter assay and functional effect was evaluated using primary mouse/human CD4+ve T-cells differentiation to Th17 cells. Pharmacokinetic profile of potent compounds was determined to support evaluation of efficacy as well as safety profile in rodents. Lead compounds have demonstrated good activity ( 100 fold selectivity against RORα as well as other nuclear receptors with significant inhibition of IL-17 release in Th17 differentiation assay. Lead compounds have shown optimal physicochemical profile including good solubility and high free fraction, leading to excellent pharmacokinetic profile in mice and rats. Efficacy of lead compounds has been demonstrated in multiple disease models including asthma, psoriasis, Experimental auto immune encephalomyelitis and collagen induced arthritis. Potential lead candidates have been identified with excellent in-vitro safety profile including CEREP-44 safety panel, Ames test and cytotoxicity. One of the lead candidates has also demonstrated good therapeutic window as determined by a 7 day rat toxicity study. Conclusions We have identified structurally diverse small molecule inverse agonists of RORγ and have demonstrated efficacy in relevant disease models as well as good therapeutic window.