Harcken Christian, Csengery Johanna, Turner Michael, Wu Lifen, Liang Shuang, Sibley Robert, Brunette Steven, Labadia Mark, Hoyt Kathleen, Wayne Anita, Wieckowski Thomas, Davis Gregg, Panzenbeck Mark, Souza Donald, Kugler Stanley, Terenzio Donna, Collin Delphine, Smith Dustin, Fryer Ryan M, Tseng Yin-Chao, Hehn Jörg P, Fletcher Kim, Hughes Robert O
Department of R&D Project Management and Development Strategies, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
Department of Small Molecule Discovery Research, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
ACS Med Chem Lett. 2021 Jan 5;12(1):143-154. doi: 10.1021/acsmedchemlett.0c00575. eCollection 2021 Jan 14.
The interleukin (IL)-23/T helper (Th)17 axis plays a critical role in autoimmune diseases, and there is an increasing number of biologic therapies that target IL-23 and IL-17. The transcription factor retinoic acid receptor-related orphan nuclear receptor γt (RORγt) is important for the activation and differentiation of Th17 cells and thus is an attractive pharmacologic target for the treatment of Th17-mediated diseases. A novel series of pyrazinone RORγ antagonists was discovered through hybridization of two distinct screening hits and scaffold hopping. The series offers attractive potency and selectivity in combination with favorable druglike properties, such as metabolic stability and aqueous solubility. Lead optimization identified a clinical candidate, compound ()- (BI 730357), for the treatment of autoimmune diseases.
白细胞介素（IL）-23/辅助性T细胞（Th）17轴在自身免疫性疾病中起关键作用，并且越来越多的生物疗法靶向IL-23和IL-17。转录因子视黄酸受体相关孤儿核受体γt（RORγt）对Th17细胞的激活和分化很重要，因此是治疗Th17介导疾病的一个有吸引力的药理学靶点。通过将两个不同的筛选命中物杂交和骨架跃迁发现了一系列新型吡嗪酮RORγ拮抗剂。该系列具有吸引人的效力和选择性，同时具有良好的类药性质，如代谢稳定性和水溶性。先导化合物优化确定了一种用于治疗自身免疫性疾病的临床候选化合物（）-（BI 730357）。
