Discovery of tetrahydroquinolines and benzomorpholines as novel potent RORγt agonists.

Abstract

The retinoic acid receptor-related orphan receptor γt (RORγt) is an important nuclear receptor that regulates the differentiation of Th17cells and production of interleukin 17(IL-17). RORγt agonists increase basal activity of RORγt and could provide a potential approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak RORγt agonist during in-house library screening. Changes in LHS core of 1 led to the identification of tetrahydroquinoline compound 6 as a partial RORγt agonist (max. act.=39.3%). Detailed structure-activity relationship on substituent of the LHS core, amide linker and RHS arylsulfonyl moiety was explored and a novel series of tetrahydroquinolines and benzomorpholines was discovered as potent RORγt agonists. Tetrahydroquinoline compound 8g (EC50=8.9±0.4nM, max. act.=104.5%) and benzomorpholine compound 9g (EC50=7.5±0.6nM, max. act.=105.8%) were representative compounds with high RORγt agonistic activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene assay and Th17cell differentiation assay (104.5% activation at 300nM of 8g; 59.4% activation at 300nM of 9g). The binding modes of 8g and 9g as well as the two RORγt inverse agonists accidentally discovered were also discussed.