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

[Display omitted] •Identification of indole analogues as potent RORγt inverse agonists, SAR of around 44 compounds is presented.•Potent compounds were evaluated for pharmacokinetic properties and data is presented.•Significant inhibition of anti-CD3/anti-CD28 induced Il17 gene expression in mouse splenocytes assay.•One of the potent compounds, RO-2 inhibited IL-17A release from (a) mouse splenocytes and (b) human whole blood with an IC50 of 503 nM and 490 nM respectively.•RO-2 was evaluated for its potential in experimental autoimmune encephalomyelitis (EAE) and psoriasis model. Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ 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 RORγt 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 RORγt, efficacious in various Th17 driven models of autoimmune disorders.