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Published on: December 27, 2024
Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists
Zheming Ruan1, Peter K Park1, Donna Wei1
1Department of Chemistry, Bristol Myers Squibb Company, P.O. Box 4000, Princeton, NJ, USA.
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.
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