新型RORγt反向激动剂的设计合成、作用机制和抗类风湿关节炎活性研究

RORγt, a member of nuclear receptor superfamily, is considered as a novel target for the Th17-related autoimmune diseases such as rheumatoid arthritis (RA). As a new way for the treatment of RA, RORγt small molecule inhibitors have recently become a hot research topic in the academic and even in some pharmaceutical companies. Previously when working in GSK, the author had identified a series of N-aryl amides as novel RORγt inverse agonists. Although exhibiting good RORγt activities, this type of compounds suffers from genotoxicity liability due to the presence of aniline moiety and could not be developed further. In this proposal, we will use the previously identified N-aryl amides as our chemical starting point to discover new series of RORγt inverse agonists with no aniline structural moiety contained through knowledge- and structure-based design. The RORγt activity and developability profile of the new lead series will be optimized for anti-RA drug candidate selection. Furthermore, with aid of crystal structure of N-aryl amide complexed with RORγt LBD, we will design and synthesize a series of RORγt agonists and so-called “short” and “long” inverse agonists in one single molecular skeleton to compare and study their binding modes, mechanism of action and effects on Th17 cell differentiation and transcriptional network inhibition in order to provide with a theoretical basis for discovery of anti-RA drugs with high efficacy and low toxicity.

孤儿核受体RORγt是抗类风湿关节炎(RA)药物研发的新靶点。作为RA治疗的新途径，RORγt小分子抑制剂近年来已成为国外学术界乃至制药公司研究的热点。申请者前期在GSK发现了N-芳基酰胺类RORγt反向激动剂，这些化合物虽然生物活性很高，但由于含有芳香胺结构片段，易产生潜在的遗传毒性。本项目以N-芳基酰胺为先导化合物，应用生物电子等排/骨架跃迁等原理，通过分子对接方法替换乙酰胺连接子，设计合成新型非芳胺类RORγt反向激动剂并对其活性及成药性进行优化，以期获得有自主知识产权、毒副作用低和抗RA药效良好的口服小分子候选药物。同时，以前期解出的N-芳基酰胺RORγt激动剂复合物晶体结构为基础，设计合成可以在同一分子骨架上变换的RORγt激动剂和“长”、“短”两类反向激动剂并比较其与受体的结合模式、作用机制以及对Th17细胞分化和转录抑制的影响，为新型高效低毒抗RA药物的研发提供理论依据。

孤儿核受体RORγt是抗自身免疫性疾病（类风湿性关节炎和银屑病等）药物研发的新靶点。RORγt小分子抑制剂近年来已成为国外学术界乃至制药公司研究的热点。本项目以N-芳基酰胺为先导化合物，应用生物电子等排/骨架跃迁等原理，设计合成新型RORγt反向激动剂，确定联芳基酰胺类、联芳基脲类、咔唑酰胺类和吲哚酰胺类等四个RORγt反向激动剂先导化合物系列，并对其活性及成药性进行优化，获得1个具有自主知识产权、口服吸收好、毒副作用低且抗自身免疫性疾病药效好的新型联芳基脲类RORγt反向激动剂候选药物YW-089，正进行临床前研究。本项目已申请多项中国发明专利和国际PCT专利，具有广阔的临床转化前景。本项目还发现左侧基团从小到大逐渐变化的联芳基类和咔唑类功能渐变RORγt调节剂探针分子，揭示了RORγt激动剂和“长”、“短”两类反向激动剂的结构变化规律。解析RORγt激动剂和“长”、“短”两类反向激动剂与RORγt LBD的复合物晶体结构，完成分子动力学模拟研究，分析引起AF2结构域构象变化的规律和小分子结合对共激活/共抑制因子的影响，及其对Th17细胞分化和转录抑制影响的作用机制，为RORγt激动剂和反向激动剂的优化设计提供指导。

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