Targeting the Nuclear Hormone Receptor RORγt for the Treatment of Autoimmune and Inflammatory Disorders

Discovery of N -(4-aryl-5-aryloxy-thiazol-2-yl)-amides as potent RORγt inverse agonists

“…5 RORt inhibitors has potential utility in reducing the activity of Th17 cells and therefore can be developed as therapeutic agents for the treatment of Th17-mediated autoimmune diseases. [7][8][9][10][11][12][13] A few small molecule inhibitors against RORt have been reported in literature. 14 Digoxin, 15 SR1001 16 and Ursolic acid 17 were firstly reported to inhibit RORt and ameliorate EAE in mice via intraperitoneal administration.…”

Benzoxazepines Achieve Potent Suppression of IL‐17 Release in Human T‐Helper 17 (TH17) Cells through an Induced‐Fit Binding Mode to the Nuclear Receptor RORγ

“…[20,[27][28][29][30] The literature, including patenta pplications, has been reviewed recently. [31][32][33] Benzannulated oxacycles of various sizes have been disclosed by Lycera and Phenex. Benzoxazocine (1,P henex) [34] and benzoxazine (2,L ycera) [35] are two representative examples, which we initially characterized ( Figure 2).…”

Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

“…Recently, anti-IL-17 biologics have been shown to be clinically effective against autoimmune diseases such as psoriasis. − As these clinical agents are monoclonal antibodies, there is still a need for small molecule oral therapies modulating IL-17. As a result, there has been much interest in small molecule inhibitors of RORγt, including inverse agonists, as a strategy to suppress IL-17. − Herein, we report our continued optimization of tricyclic inverse agonists of RORγt, which culminated in the identification of a viable clinical candidate.…”