Cao Ruolin, Du Fangyu, Liu Zhiqiang, Cai Pengcheng, Qi Minggang, Xiao Wei, Bao Xuefei, Chen Guoliang
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University Shenyang 110016 PR China
Jiangsu Kanion Pharmaceutical Co., Ltd., Jiangning Industrial City Economic and Technological Development Zone Lianyungang Jiangsu 222001 China.
RSC Med Chem. 2024 Aug 1;15(10):3576-96. doi: 10.1039/d4md00438h.
Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound DC24 was identified as the optimal hit in enzymatic screening with an IC value of 0.124 μM against ROCK2 and 50-fold selectivity over ROCK1. DC24 has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and DC24 is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of DC24 with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, DC24 at a dose of 5 mg kg exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, DC24 exhibits good safety .
Rho相关卷曲螺旋蛋白激酶（ROCK）在炎症中起重要作用。在此，基于基于结构的药物设计（SBDD）策略设计并合成了一系列化合物作为ROCK抑制剂，并对其细胞毒性、抗氧化活性和抗炎活性进行了评估。其中，化合物DC24在酶筛选中被确定为最佳命中物，对ROCK2的IC值为0.124 μM，对ROCK1的选择性为50倍。DC24具有带有双（4-氟苯基）甲基取代基的新型脂质酰胺支架，并且DC24是第一个与ROCK2的铰链区——1,2-二硫杂环戊烷-3-基基序相互作用的ROCK2抑制剂，这已通过DC24与ROCK2的结合模型得到证实。在完全弗氏佐剂（CFA）诱导的急性炎症模型中，5 mg/kg剂量的DC24表现出比贝莫司他更好的抗炎作用。此外，DC24表现出良好的安全性。
