Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure–activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.

合成了新颖的小分子，并作为视黄酸受体相关的孤儿受体-γt（RORγt）反向激动剂进行了评估，用于治疗炎症和自身免疫性疾病。通过对我们的化合物库进行高通量筛选，发现了一种命中化合物1。化合物1的结构-活性关系（SAR）研究表明，在4-氰基苯基部分的3-位引入氯基可提高效能，而3-甲基戊烷-1,5-二酰胺连接基有利于活性。还优化了1的咔唑部分；喹唑啉二酮衍生物18i抑制大鼠口服实验性自身免疫性脑脊髓炎（EAE）模型淋巴结中IL-17A mRNA水平的升高。这些结果表明，新颖的喹唑啉二酮衍生物作为口服可用的小分子RORγt反向激动剂具有巨大的潜力，可用于治疗Th17驱动的自身免疫性疾病。还观察到该化学型与RORγt蛋白的U形生物活性构象。