Identification of N-sulfonyl-tetrahydroquinolines as RORc inverse agonists.

Abstract 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.