Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
Eur J Med Chem. 2023 Aug 5;256:115424. doi: 10.1016/j.ejmech.2023.115424. Epub 2023 Apr 29.
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 compound 1 was 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 IC values in the range of 7 nM-50 nM in RORγt dual FRET assay. Among them, compound 14g displayed potent RORγt inverse agonistic activity with an IC value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC value of 0.428 μM 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 (AUC = 5058 ng/mL*h). Most importantly, 14g alleviated 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.
维甲酸受体相关孤儿受体 γt（RORγt）已被用作治疗炎症和自身免疫性疾病的新小分子治疗药物的有前途的靶标，通过调节辅助性 T 细胞 17（Th17）细胞产生白介素-17（IL-17）。在此，我们报告了一系列基于三嗪的衍生物，作为新型 RORγt 反向激动剂。通过筛选我们的内部化合物库，鉴定出具有弱 RORγt 抑制活性的命中化合物 1。随后，我们对三嗪衍生物进行了详细的结构修饰，以探索其构效关系（SARs），从而发现了一系列具有 IC 值在 7 nM-50 nM范围内的有效的 RORγt 反向激动剂在 RORγt 双荧光素酶测定中。其中，化合物 14g 在双荧光素酶测定中表现出很强的 RORγt 反向激动活性，IC 值为 22.9 nM。在基于细胞的报告基因测定中，化合物 14g 的 IC 值为 0.428 μM，最大抑制率为 108.9%。化合物 14g 还表现出良好的代谢稳定性和相当的药代动力学特征，清除率（CL = 0.229 L/h/kg）低，口服暴露（AUC = 5058 ng/mL*h）合理。最重要的是，14g 减轻了咪喹莫特诱导的小鼠银屑病的严重程度。总之，基于三嗪的衍生物代表了一类新的 RORγt 反向激动剂，作为治疗自身免疫性疾病的潜在治疗药物。
