Discovery and structural optimization of 4-（ 4-（ benzyloxy）p henyl）-3,4-dihyd ropyrimidin-2（1H ）- ones as RORc inverse agonists  

作　　者：Xi-shan WU Rui WANG Yan-li XING Xiao-qian XUE Yan ZHANG Yong-zhi LU Yu SONG Xiao-yu LUO Chun WU Yu-lai ZHOU Jian-qin JIANG Yong XU 

机构地区：[1]Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China [2]Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China [3]University of Chinese Academy of Sciences, Beijing 100049, China [4]Department of Bioengineering, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China

出　　处：《Acta Pharmacologica Sinica》2016年第11期1516-1524,共9页中国药理学报（英文版）

基　　金：We gratefully acknowledge financial support partly from the National Natural Science Foundation of China （81373325）, the ＂100 Talents Project＂ of Chinese Academy of Sciences, the Natural Science Foundation of Guangdong Province （c15140600000016）, the Guangzhou Healthcare Collaborative Innovation Programs （201508020255）, the Chinese Academy of Sciences Cloud Platform for Stem Cell and BiomedicalResearch （XXH12503-05-06）, the National Key Basic Research Program of China （973 Program, 2013CB910601） and Bureau of Science and Information Technology of Guangzhou Municipality （2013J4500008）. The authors gratefully acknowledge support from the Guangzhou Branch of the Supercomputing Center of Chinese Academy of Sciences.

摘　　要：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 IC50 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.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 IC50 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.

关 键 词：nuclear receptor RORC inverse agonist SAR structure-based optimization autoimmune disease 

分 类 号：R[医药卫生]