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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]