Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists. (1st March 2021)

• Record Type: Journal Article
• Authors: Ruan, Zheming; Park, Peter K.; Wei, Donna; Purandare, Ashok; Wan, Honghe; O'Malley, Daniel; Stachura, Sylwia; Perez, Heidi; Cavallaro, Cullen L.; 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; Xie, Jenny H.; Anthony, Monique; Agler, Michele; Fink, Brian E.; Harikrishnan, Lalgudi S.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 35(2021)
• Publication Date: 2021-03-01
• Subjects: RORγt -- RORgt -- ROR gamma -- Retinoic acid related-orphan receptor -- Th 17 cells and IL-17; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127778
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.