Liu Qingjie, Xiao Hai-Yun, Batt Douglas G, Xiao Zili, Zhu Yeheng, Yang Michael G, Li Ning, Yip Shiuhang, Li Peng, Sun Dawn, Wu Dauh-Rurng, Ruzanov Max, Sack John S, Weigelt Carolyn A, Wang Jinhong, Li Sha, Shuster David J, Xie Jenny H, Song Yunling, Sherry Tara, Obermeier Mary T, Fura Aberra, Stefanski Kevin, Cornelius Georgia, Chacko Silvi, Khandelwal Purnima, Dudhgaonkar Shailesh, Rudra Anjuman, Nagar Jignesh, Murali Venkata, Govindarajan Arun, Denton Rex, Zhao Qihong, Meanwell Nicholas A, Borzilleri Robert, Dhar T G Murali
Research and Early Development, Bristol Myers Squibb Company, Princeton, New Jersey 08540-4000, United States.
Biocon Bristol Myers Squibb Research Centre, Biocon Park, Bommasandra IV Phase, Jigani Link Road, Bengaluru 560099, India.
ACS Med Chem Lett. 2021 Apr 30;12(5):827-835. doi: 10.1021/acsmedchemlett.1c00112. eCollection 2021 May 13.
Structure-activity relationship studies directed toward the replacement of the fused phenyl ring of the lead hexahydrobenzoindole RORγt inverse agonist series represented by with heterocyclic moieties led to the identification of three novel aza analogs -. The hexahydropyrrolo[3,2-]quinoline series (X = N, Y = Z=CH) showed potency and metabolic stability comparable to series but with improved membrane permeability and serum free fraction. This structural modification was applied to the hexahydrocyclopentanaphthalene series , culminating in the discovery of as a potent and selective RORγt inverse agonist with an excellent profile, good pharmacokinetic properties, and biologic-like efficacy in preclinical models of rheumatoid arthritis and psoriasis.
针对用杂环部分取代以 为代表的先导六氢苯并吲哚RORγt反向激动剂系列的稠合苯环进行的构效关系研究，导致鉴定出三种新型氮杂类似物 - 。六氢吡咯并[3,2 - ]喹啉系列 （X = N，Y = Z = CH）显示出与系列 相当的效力和代谢稳定性，但具有改善的膜通透性和血清游离分数。这种结构修饰应用于六氢环戊并萘系列 ，最终发现 是一种强效且选择性的RORγt反向激动剂，在类风湿性关节炎和牛皮癣的临床前模型中具有优异的 谱、良好的药代动力学性质和类生物 效力。
