Zhu Junsheng, Han Le, Diao Yanyan, Ren Xiaoli, Xu Minghao, Xu Liuxin, Li Shiliang, Li Qiang, Dong Dong, Huang Jin, Liu Xiaofeng, Zhao Zhenjiang, Wang Rui, Zhu Lili, Xu Yufang, Qian Xuhong, Li Honglin
State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, and ‡Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
J Med Chem. 2015 Feb 12;58(3):1123-39. doi: 10.1021/jm501127s. Epub 2015 Jan 26.
Human dihydroorotate dehydrogenase (HsDHODH) is a flavin-dependent mitochondrial enzyme that has been certified as a potential therapeutic target for the treatment of rheumatoid arthritis and other autoimmune diseases. On the basis of lead compound 4, which was previously identified as potential HsDHODH inhibitor, a novel series of thiazole derivatives were designed and synthesized. The X-ray complex structures of the promising analogues 12 and 33 confirmed that these inhibitors bind at the putative ubiquinone binding tunnel and guided us to explore more potent inhibitors, such as compounds 44, 46, and 47 which showed double digit nanomolar activities of 26, 18, and 29 nM, respectively. Moreover, 44 presented considerable anti-inflammation effect in vivo and significantly alleviated foot swelling in a dose-dependent manner, which disclosed that thiazole-scaffold analogues can be developed into the drug candidates for the treatment of rheumatoid arthritis by suppressing the bioactivity of HsDHODH.
人二氢乳清酸脱氢酶（HsDHODH）是一种依赖黄素的线粒体酶，已被确认为治疗类风湿性关节炎和其他自身免疫性疾病的潜在治疗靶点。基于先前被鉴定为潜在HsDHODH抑制剂的先导化合物4，设计并合成了一系列新型噻唑衍生物。有前景的类似物12和33的X射线复合物结构证实，这些抑制剂结合在假定的泛醌结合通道处，并引导我们探索更有效的抑制剂，如化合物44、46和47，它们分别表现出26、18和29 nM的两位数纳摩尔活性。此外，44在体内呈现出相当大的抗炎作用，并以剂量依赖的方式显著减轻足部肿胀，这表明噻唑骨架类似物可通过抑制HsDHODH的生物活性而开发成为治疗类风湿性关节炎的候选药物。
