Annulation reaction enables the identification of an exocyclic amide tricyclic chemotype as retinoic acid Receptor-Related orphan receptor gamma (RORγ/RORc) inverse agonists

[Display omitted] RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the...

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Published in:Bioorganic & medicinal chemistry letters 2020-10, Vol.30 (19), p.127466-127466, Article 127466
Main Authors: Marcoux, David, Bertrand, Myra Beaudoin, Weigelt, Carolyn A., Yip, Shiuhang, Galella, Michael, Park, Hyunsoo, Wu, Dauh-Rurng, Wang, Jinhong, Yarde, Melissa, Cvijic, Mary Ellen, Li, Sha, Hynes, John, Tino, Joseph A., Zhao, Qihong, Dhar, T.G. Murali
Format: Article
Language:English
Subjects:
Annulation
Cyclopentane
Exocyclic amide
IL-17
RORγt
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Summary:[Display omitted] RORγt is the master regulator of the IL-23/IL-17 axis, a pathway that is clinically validated for the treatment of various immunological disorders. Over the last few years, our group has reported different chemotypes that potently act as inverse agonists of RORγt. One of them, the tricyclic pyrrolidine chemotype, has demonstrated biologic-like preclinical efficacy and has led to our clinical candidate BMS-986251. In this letter, we discuss the invention of an annulation reaction which enabled the synthesis of a tricyclic exocyclic amide chemotype and the identification of compounds with RORγt inverse agonist activity. Preliminary structure activity relationships are disclosed.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2020.127466