作者
Zheming Ruan,Peter J. Park,Donna D. Wei,Ashok V. Purandare,Honghe Wan,Daniel O'Malley,Sylwia Stachura,Heidi L. Perez,Cullen L. Cavallaro,Carolyn A. Weigelt,John S. Sack,Max Ruzanov,Javed Khan,Murali Gururajan,Jessica J. Wong,Yanling Huang,Melissa Yarde,Zhuyin Li,Cliff Chen,Huadong Sun,Virna Borowski,Jenny Xie,Monique Anthony,Michele Agler,Brian Fink,Lalgudi S. Harikrishnan
摘要
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.