Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
Eur J Med Chem. 2020 Sep 15;202:112536. doi: 10.1016/j.ejmech.2020.112536. Epub 2020 Jul 5.
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 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.
GSK805（1）是一种有效的 RORγt 反向激动剂，但 1 的一个缺点是其溶解度低，导致高剂量时吸收有限。我们已经探索了 1 的酰胺连接基、联苯和芳基砜部分的详细结构-活性关系，试图在保持 RORγt 活性的同时提高溶解度。结果，发现了一系列新型含羧基联苯脲衍生物，它们是有效的 RORγt 反向激动剂，具有改善的类药性。化合物 3i 在 RORγ FRET 测定和基于细胞的 RORγ-GAL4 启动子报告测定中显示出对 RORγt 的抑制活性和亚型选择性，IC 值分别为 63.8 nM 和 85 nM。3i 在小鼠 Th17 细胞分化测定中也显示出合理的抑制活性（在 0.3 μM 时抑制率为 76%）。此外，与 1 相比，3i 在 pH 7.4 时的水溶解度大大提高，具有良好的小鼠 PK 特征，并在咪喹莫特诱导的银屑病小鼠模型中显示出一定的体内疗效。
