Discovery of carboxyl-containing biaryl ureas as potent ROR?t inverse agonists.

Sun N, Huang Y, Yu M, Zhao Y, Chen JA, Zhu C, Song M, Guo H, Xie Q, Wang Y. Discovery of carboxyl-containing biaryl ureas as potent ROR?t inverse agonists. European journal of medicinal chemistry. 2020 Sep 15; 202:112536.

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Abstract:

GSK805 (1) is a potent ROR?t 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 ROR?t activity. As a result, a novel series of carboxyl-containing biaryl urea derivatives was discovered as potent ROR?t inverse agonists with improved drug-like properties. Compound 3i showed potent ROR?t inhibitory activity and subtype selectivity with an IC of 63.8 nM in ROR? FRET assay and 85 nM in cell-based ROR?-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.