1. Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists
- Author
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Yanling Huang, Murali Gururajan, Cullen L. Cavallaro, Zhuyin Li, Ashok V. Purandare, Jessica J. Wong, Jenny Xie, Sylwia Stachura, Huadong Sun, Lalgudi S. Harikrishnan, Javed Khan, Brian E. Fink, Carolyn A. Weigelt, Honghe Wan, Peter K. Park, Daniel O'malley, Michele Agler, Cliff Chen, John S. Sack, Donna D. Wei, Zheming Ruan, Melissa Yarde, Heidi L. Perez, Monique Anthony, Virna Borowski, and Max Ruzanov
- Subjects
Models, Molecular ,Agonist ,medicine.drug_class ,Clinical Biochemistry ,Retinoic acid ,Pharmaceutical Science ,Tretinoin ,Pharmacology ,Crystallography, X-Ray ,01 natural sciences ,Biochemistry ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pharmacokinetics ,RAR-related orphan receptor gamma ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Molecular Biology ,Orphan receptor ,Diaryl ether ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Th17 Cells ,Molecular Medicine ,Lead compound ,Ethers - 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.
- Published
- 2021