Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists.
Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists.
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DOI：
10.1016/j.ejmech.2023.115424
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发表时间：
2023-04
影响因子：
6.7
通讯作者：
Lixue Lu;Song Chen;Ming-cheng Yu;Ronghui Zhou;Si-qi Guo;Ji-an Chen;Haojie Wang;Shijie Chen;Cheng Luo;Qiong Xie;Yonghui Wang
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文献类型：
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作者：
Lixue Lu;Song Chen;Ming-cheng Yu;Ronghui Zhou;Si-qi Guo;Ji-an Chen;Haojie Wang;Shijie Chen;Cheng Luo;Qiong Xie;Yonghui Wang
Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) 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 RORγt inverse agonists. By screening of our in-house compound library, the hit compound1was identified with weak RORγt 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 RORγt inverse agonists with IC50values in the range of 7 nM–50 nM in RORγt dual FRET assay. Among them, compound14gdisplayed potent RORγt inverse agonistic activity with an IC50value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound14gshowed an IC50value of 0.428 μM and maximum inhibition rate of 108.9%. Compound14galso 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,14galleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazine-based derivatives represent a new chemical class of RORγt inverse agonists as potential therapeutic agents against autoimmune diseases.
