Discovery of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new ROR gamma inhibitors using virtual screening, synthesis and biological evaluation
Discovery of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new ROR gamma inhibitors using virtual screening, synthesis and biological evaluation
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通过虚拟筛选、合成和生物学评价发现 2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺衍生物作为新型 ROR γ 抑制剂
DOI：
10.1016/j.ejmech.2014.03.065
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发表时间：
2014
影响因子：
6.7
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Zhang Yan;Xue Xiaoqian;Jin Xiangyu;Song Yu;Li Jing;Luo Xiaoyu;Song Ming;Yan Weiqun;Song Hongrui;Xu Yong
视黄酸受体相关孤儿受体 γ (RORγ) 是核激素受体超家族的成员，是治疗 Th17 介导的自身免疫性疾病的有前景的治疗靶点。我们针对 RORγ 配体结合域进行了基于结构的虚拟筛选。在测试的化合物中，s4 在 AlphaScreen 测定 (20.27 μM) 和基于细胞的报告基因测定 (11.84 μM) 中均显示出具有微摩尔 IC50 值的 RORγ 拮抗活性。对这 4 个化合物的优化导致了化合物 7j、8c、8k 和 8p 的鉴定，所有这些化合物都显示出显着增强的 RORγ 抑制作用，IC50 值为 40–140 nM。这些结果为开发有效的小分子 RORγ 抑制剂提供了一个有希望的起点。
Retinoic acid receptor-related orphan receptor γ (RORγ), a member of the nuclear hormone receptor superfamily, is a promising therapeutic target for treating Th17-mediated autoimmune diseases. We performed structure-based virtual screening targeting the RORγ ligand-binding domain. Among the tested compounds, s4 demonstrated RORγ antagonistic activities with micromolar IC50values in both an AlphaScreen assay (20.27 μM) and a cell-based reporter gene assay (11.84 μM). Optimization of thes4compound led to the identification of compounds7j,8c,8k, and8p, all of which displayed significantly enhanced RORγ inhibition with IC50values of 40–140 nM. These results represent a promising starting point for developing potent small molecule RORγ inhibitors.