Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORγt) agonists. Issue 12 (15th June 2020)

• Record Type: Journal Article
• Authors: Harikrishnan, Lalgudi S.; Gill, Patrice; Kamau, Muthoni G.; Qin, Lan-Ying; Ruan, Zheming; O'Malley, Daniel; Huynh, Tram; Stachura, Sylwia; Cavallaro, Cullen L.; Lu, Zhonghui; J.-W. Duan, James; Weigelt, Carolyn A.; Sack, John S.; Ruzanov, Max; Khan, Javed; Gururajan, Murali; Wong, Jessica J.; Huang, Yanling; Yarde, Melissa; Li, Zhuyin; Chen, Cliff; Sun, Huadong; Borowski, Virna; Murtaza, Anwar; Fink, Brian E.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 12(2020)
• Publication Date: 2020-06-15
• Subjects: RORγt -- RORgt -- ROR gamma -- Retinoic acid related orphan receptor -- TH17 cells and IL-17; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127204
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.