Discovery and pharmacological evaluation of indole derivatives as potent and selective RORγt inverse agonist for multiple autoimmune conditions

Abstract Targeting nuclear receptorRORγ is recognized to be beneficial in multiple autoimmunedisorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailablecompounds was evaluated in various models of autoimmunedisorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmunediseases. The results indicate the potential of these indole analogues as orally bioavailablesmall molecule inverse agonistsof RORγt, efficacious in various Th17 driven models of autoimmunedisorders.