Marcoux David, Bertrand Myra Beaudoin, Weigelt Carolyn A, Yip Shiuhang, Galella Michael, Park Hyunsoo, Wu Dauh-Rurng, Wang Jinhong, Yarde Melissa, Cvijic Mary Ellen, Li Sha, Hynes John, Tino Joseph A, Zhao Qihong, Dhar T G Murali
Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ 08540, United States.
Research and Early Development, Bristol Myers Squibb, 3551 Lawrenceville Rd, Princeton, NJ 08540, United States.
Bioorg Med Chem Lett. 2020 Oct 1;30(19):127466. doi: 10.1016/j.bmcl.2020.127466. Epub 2020 Aug 5.
RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.
RORγt是IL-23/IL-17轴的主要调节因子，该信号通路在治疗各种免疫性疾病方面已得到临床验证。在过去几年中，我们团队报道了多种具有强效RORγt反向激动剂活性的化学类型。其中之一，三环吡咯烷化学类型，已显示出类似生物制剂的临床前疗效，并促使我们研发出临床候选药物BMS-986251。在本信函中，我们讨论了一种环化反应的发明，该反应能够合成三环外环酰胺化学类型，并鉴定出具有RORγt反向激动剂活性的化合物。文中还披露了初步的构效关系。
