Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists

Retinoic Acid Receptor-Related Orphan Receptor gamma t (ROR gamma t) has been exploited as a promising target for the new small molecule therapeutics to treat inflammatory and autoimmune diseases via modulating the interleukin-17 (IL-17) production by T helper 17 (Th17) cells. Herein, we reported a series of triazine-based derivatives as novel ROR gamma t inverse agonists. By screening of our in-house compound library, the hit compound 1 was identified with weak ROR gamma t inhibitory activity. Subsequently, we engineered detailed structural modifications to explore the structure-activity relationships (SARs) of triazines derivatives, which led to discovery of a number of potent ROR gamma t inverse agonists with IC50 values in the range of 7 nM-50 nM in ROR gamma t dual FRET assay. Among them, compound 14g displayed potent ROR gamma t inverse agonistic activity with an IC50 value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC50 value of 0.428 mu M and maximum inhibition rate of 108.9%. Compound 14g also exhibited good metabolic stability and a decent pharmacokinetic profile with a low clearance (CL = 0.229 L/h/kg) and a reasonable oral exposure (AUC0- Last = 5058 ng/mL*h). Most importantly, 14g alleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazinebased derivatives represent a new chemical class of ROR gamma t inverse agonists as potential therapeutic agents against autoimmune diseases.

Automated summary

Retinoic Acid Receptor-Related Orphan Receptor gamma t (ROR γ t) has been proposed as a potential target for the treatment of inflammatory and autoimmune diseases by regulating the production of interleukin-17 (IL-17) by T helper 17 (Th17) cells. In this study, a series of triazine-based derivatives were developed as novel ROR γ t inverse agonists. Compound 14g exhibited potent ROR γ t inverse agonistic activity and showed promising therapeutic potential in treating autoimmune diseases.