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ID: ALA4699477
Journal: Bioorg Med Chem Lett
Title: Tricyclic sulfones as potent, selective and efficacious RORγt inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization.
Authors: Shi Q,Xiao Z,Yang MG,Marcoux D,Cherney RJ,Yip S,Li P,Wu DR,Weigelt CA,Sack J,Khan J,Ruzanov M,Wang J,Yarde M,Ellen Cvijic M,Li S,Shuster DJ,Xie J,Sherry T,Obermeier M,Fura A,Stefanski K,Cornelius G,Chacko S,Shu YZ,Khandelwal P,Hynes J,Tino JA,Salter-Cid L,Denton R,Zhao Q,Dhar TGM
Abstract: 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.
CiteXplore: 32882417