Медицинская библиотека · Bioorganic & medicinal chemistry letters · 2020

Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization.

Shi Qing, Xiao Zili, Yang Michael G, Marcoux David, Cherney Robert J, Yip Shiuhang, Li Peng, Wu Dauh-Rurng, Weigelt Carolyn A, Sack John, Khan Javed, Ruzanov Max, Wang Jinhong, Yarde Melissa, Ellen Cvijic Mary, Li Sha, Shuster David J, Xie Jenny, Sherry Tara, Obermeier Mary, Fura Aberra, Stefanski Kevin, Cornelius Georgia, Chacko Silvi, Shu Yue-Zhong, Khandelwal Purnima, Hynes John, Tino Joseph A, Salter-Cid Luisa, Denton Rex, Zhao Qihong, Dhar T G Murali

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Аннотация

In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.

Для цитирования: Shi Qing, Xiao Zili, Yang Michael G, Marcoux David, Cherney Robert J, Yip Shiuhang, Li Peng, Wu Dauh-Rurng, Weigelt Carolyn A, Sack John, Khan Javed, Ruzanov Max, Wang Jinhong, Yarde Melissa, Ellen Cvijic Mary, Li Sha, Shuster David J, Xie Jenny, Sherry Tara, Obermeier Mary, Fura Aberra, Stefanski Kevin, Cornelius Georgia, Chacko Silvi, Shu Yue-Zhong, Khandelwal Purnima, Hynes John, Tino Joseph A, Salter-Cid Luisa, Denton Rex, Zhao Qihong, Dhar T G Murali. Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization.. Bioorganic & medicinal chemistry letters. 2020. DOI: 10.1016/j.bmcl.2020.127521.

Предметные рубрики MeSH

Animals Crystallography, X-Ray Drug Inverse Agonism Female Heterocyclic Compounds, 3-Ring Interleukin-18 Male Melanosis Mice, Inbred BALB C Mice, Inbred C57BL Molecular Structure Nuclear Receptor Subfamily 1, Group F, Member 3 Protein Binding Structure-Activity Relationship Sulfones

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