Sun, Nannan; Huang, Yafei; Yu, Mingcheng; Zhao, Yunpeng; Chen, Ji-An; Zhu, Chenyu; Song, Meiqi; Guo, Huimin; Xie, Qiong; Wang, Yonghui published the artcile< Discovery of carboxyl-containing biaryl ureas as potent RORγt inverse agonists>, Application In Synthesis of 215949-57-8, the main research area is autoimmune diseases ROR gamma t inverse agonists Th17 cells; Autoimmune diseases; Biaryl ureas; Inverse agonists; RORγt; Th17 cells.
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(I) showed potent RORγt inhibitory activity and subtype selectivity with an IC50 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.
European Journal of Medicinal Chemistry published new progress about Autoimmune disease. 215949-57-8 belongs to class bromides-buliding-blocks, and the molecular formula is C9H9BrO2, Application In Synthesis of 215949-57-8.
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary