Discovery of novel N-sulfonamide-tetrahydroquinolines as potent retinoic acid receptor-related orphan receptor gamma t inverse agonists for the treatment of autoimmune diseases

摘要

Targeting the nuclear receptor ROR gamma t is thought to be effective in autoimmune disorders. Tertiary sulfonamide 1 was found to be a potent ROR gamma t inverse agonist previously. However, the high hepatic clearance value limits its druggability. In this study, we designed and synthesized a series of N-sulfonamide-tetrahydroquinolines by molecular modeling and scaffold hopping strategy, aiming at improving the metabolic stabilities. Detailed SAR exploration led to identification of potent ROR gamma t inverse agonists such as 13 with moderate binding affinity and inhibitory activity of Th17 cell differentiation. Binding mode of 13 with ROR gamma t-LBD was revealed by molecular docking. Moreover, 13 showed lower intrinsic clearance in mouse liver microsomes compared with 1 and potent in vivo efficacy and safety in psoriasis models, which can be used as a good starting point for the further optimization. (C) 2019 Elsevier Masson SAS. All rights reserved.