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

摘要

Targeting nuclear receptor ROR gamma is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent ROR gamma inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of ROR gamma t activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of ROR gamma t, efficacious in various Th17 driven models of autoimmune disorders.