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The retinoic acid receptor-related orphan receptor γt (RORγt) is an important nuclear receptor that regulates the differentiation of Th17 cells 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 (EC 50 = 8.9 ± 0.4 nM, max. act. = 104.5%) and benzomorpholine compound 9g (EC 50 = 7.5 ± 0.6 nM, 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 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 RORγt inverse agonists accidentally discovered were also discussed. Image 1 • A series of tetrahydroquinolines and benzomorpholines was discovered as novel RORγt agonists. • The structure-activity relationships of the left-hand-side moiety, linker and right-hand-side moiety were explored. • The representative lead compounds 8g and 9g showed greatly increased RORγt agonistic activity in dual FRET assay. • 8g and 9g also performed good RORγt agonistic effect in Gal4 reporter gene assay and Th17 cell differentiation assay. • The binding modes of 8g and 9g in RORγt ligand binding domain were discussed by docking studies. [ABSTRACT FROM AUTHOR]

GSK805 (1) is a potent RORγt inverse agonist, but a drawback of 1 is its low solubility, leading to a limited absorption in high doses. We have explored detailed structure-activity relationship on the amide linker, biaryl and arylsulfonyl moieties of 1 trying to improve solubility while maintaining RORγt activity. As a result, a novel series of carboxyl-containing biaryl urea derivatives was discovered as potent RORγt inverse agonists with improved drug-like properties. Compound 3i showed potent RORγt inhibitory activity and subtype selectivity with an IC 50 of 63.8 nM in RORγ FRET assay and 85 nM in cell-based RORγ-GAL4 promotor reporter assay. Reasonable inhibitory activity of 3i was also achieved in mouse Th17 cell differentiation assay (76% inhibition at 0.3 μM). Moreover, 3i had greatly improved aqueous solubility at pH 7.4 compared to 1 , exhibited decent mouse PK profile and demonstrated some in vivo efficacy in an imiquimod-induced psoriasis mice model. Image 1 • A series of carboxyl-containing biaryl ureas was discovered as novel RORγt inverse agonists. • 3i exhibited greatly improved aqueous solubility compared to the lead compound 1 (GSK805). • 3i showed potent RORγt inhibitory activity in FRET assay and in Th17-cell based assay. • 3i demonstrated good in vivo PK profile in mice and in vivo efficacy in IMQ-induced psoriasis mice model. [ABSTRACT FROM AUTHOR]