A high-throughput screen of the Genentech/Roche compound collection using a retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) biochemical assay revealed a N-sulfonyl-tetrahydroquinoline hit. Herein, we describe the hit-to-lead optimization and structure-activity relationships of these tetrahydroquinoline RORc inverse agonists. Through iterative synthesis and analog design, we identified compounds with improved biochemical RORc inverse agonist activity and RORc cellular potencies. These improved N-sulfonyl-tetrahydroquinoline compounds also exhibited selectivity for RORc over other nuclear receptors.
CITATION STYLE
Fauber, B. P., Gobbi, A., Savy, P., Burton, B., Deng, Y., Everett, C., … Wong, H. (2015). Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists. Bioorganic and Medicinal Chemistry Letters, 25(19), 4109–4113. https://doi.org/10.1016/j.bmcl.2015.08.028
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