Discovery of tetrahydroquinolines and benzomorpholines as novel potent RORγt agonists

The retinoic acid receptor-related orphan receptor gamma t (ROR gamma t) is an important nuclear receptor that regulates the differentiation of Th17 cells and production of interleukin 17(IL-17). ROR gamma t agonists increase basal activity of ROR gamma t and could provide a potential approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak ROR gamma t agonist during in-house library screening. Changes in LHS core of 1 led to the identification of tetrahydroquinoline compound 6 as a partial ROR gamma t 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 ROR gamma t agonists. Tetrahydroquinoline compound 8g (EC50 = 8.9 +/- 0.4 nM, max. act. = 104.5%) and benzomorpholine compound 9g (EC50 = 7.5 +/- 0.6 nM, max. act. = 105.8%) were representative compounds with high ROR gamma t agonistic activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene assay and Th17 cell differentiation assay (104.5% activation at 300 nM of 8g; 59.4% activation at 300 nM of 9g). The binding modes of 8g and 9g as well as the two ROR gamma t inverse agonists accidentally discovered were also discussed. (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

ROR gamma t agonists, such as tetrahydroquinoline compound 8g and benzomorpholine compound 9g, were identified as potent compounds with high ROR gamma t agonistic activity. These compounds showed good activity in various assays and may have potential for cancer immunotherapy.