Discovery and structural optimization of 4-(4-(benzyloxy) phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists
Discovery and structural optimization of 4-(4-(benzyloxy) phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists
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作为 RORc 反向激动剂的 4-(4-(苄氧基)苯基)-3,4-二氢嘧啶-2(1H)-酮的发现和结构优化
DOI：
10.1038/aps.2016.32
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发表时间：
2016
影响因子：
8.2
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Wu Xi-shan;Wang Rui;Xing Yan-li;Xue Xiao-qian;Zhang Yan;Lu Yong-zhi;Song Yu;Luo Xiao-yu;Wu Chun;Zhou Yu-lai;Jiang Jian-qin;Xu Yong
目的：维甲酸受体相关孤儿核受体（ROR）是孤儿核受体，在缺乏配体的情况下显示组成性活性。在ROR的3种亚型中，RORc是治疗Th 17介导的自身免疫性疾病的有希望的治疗靶点。方法：以RORa激动剂化合物8的结构为基础，设计并合成了一系列4-（4-苄氧基苯基）-3，4-二氢嘧啶-2（1H）-酮衍生物。使用AlphaScreen测定法在分子水平上检测化合物与RORc之间的相互作用。在用RORc和荧光素酶报告基因转染的293 T细胞中进一步检查化合物。结果：共设计并合成了27个衍生物，并通过热稳定性变化实验考察了它们对蛋白质稳定性的影响。其中，化合物22 b被鉴定为最有效的RORc反向激动剂。AlphaScreen法测定其IC 50为2.39 μmol/L，对细胞荧光素酶报告基因活性的抑制IC 50为0.82 μmol/L。此外，化合物22 b对RORc的选择性是其他核受体的120倍。结论：4-（4-苄氧基）苯基）-3，4-二氢嘧啶-2（1H）-酮衍生物有望成为治疗类风湿关节炎、银屑病、多发性硬化等Th 17介导的自身免疫性疾病的候选药物。
Aim:Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design.Methods:Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy) phenyl)-3, 4-dihydropyrimidin-2 (1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability.Results:A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC 50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc.Conclusion:4-(4-(Benzyloxy) phenyl)-3, 4-dihydropyrimidin-2 (1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.