Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists – Exploring C6 and C8 SAR using late-stage functionalization. Issue 23 (1st December 2020)

• Record Type: Journal Article
• Authors: Shi, Qing; Xiao, Zili; Yang, Michael G.; Marcoux, David; Cherney, Robert J.; Yip, Shiuhang; Li, Peng; Wu, Dauh-Rurng; Weigelt, Carolyn A.; Sack, John; Khan, Javed; Ruzanov, Max; Wang, Jinhong; Yarde, Melissa; Ellen Cvijic, Mary; Li, Sha; Shuster, David J.; Xie, Jenny; Sherry, Tara; Obermeier, Mary; Fura, Aberra; Stefanski, Kevin; Cornelius, Georgia; Chacko, Silvi; Shu, Yue-Zhong; Khandelwal, Purnima; Hynes, John; Tino, Joseph A.; Salter-Cid, Luisa; Denton, Rex; Zhao, Qihong; Dhar, T.G. Murali;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 23(2020)
• Publication Date: 2020-12-01
• Subjects: RORγt -- Inverse agonist -- Acanthosis -- Late-stage functionalization; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127521
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.