Structural highlights
FunctionRORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock. Publication Abstract from PubMedIn order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORgammat 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 RORgammat inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed. Tricyclic Sulfones as Potent, Selective and Efficacious RORgammat Inverse Agonists - Exploring C6 and C8 SAR Using Late-Stage Functionalization.,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 Jr, Tino JA, Salter-Cid L, Denton R, Zhao Q, Murali Dhar TG Bioorg Med Chem Lett. 2020 Aug 31:127521. doi: 10.1016/j.bmcl.2020.127521. PMID:32882417[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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