Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, California 95616, United States.
J Med Chem. 2023 Feb 23;66(4):2979-3009. doi: 10.1021/acs.jmedchem.2c01996. Epub 2023 Jan 23.
Soluble epoxide hydrolase (sEH) has been identified as an attractive target for anti-inflammatory drug design in recent years. Picomolar level compound against sEH was obtained by introducing the hydrophilic group homopiperazine and hydrophobic fragment propionyl onto the structure of lead compound . showed good microsomal stability, a moderate plasma protein binding rate, and good oral bioavailability and was well tolerated in rats. has significant analgesic effects on CFA-induced AIA mice, ameliorated the pancreatic injury in acute pancreatitis induced by l-arginine, reversed pancreatic injury, edema, and neutrophil infiltration, and increased the survival time of C57BL/6 mice in a lipopolysaccharide (LPS)-induced sepsis model. Moreover the expression levels of sEH, COX-2, NOS-2, vascular cell adhesion molecule (VCAM), IL-6, MCP-5, and tumor necrosis factor α (TNF-α) were measured by Western blot or enzyme-linked immunosorbent assay (ELISA), with varying degrees of decrease. These results suggested that is a drug candidate worthy of further evaluation for the treatment of inflammation-induced diseases such as arthritis, acute pancreatitis, and sepsis.
近年来，可溶性环氧化物水解酶（sEH）已被确定为抗炎药物设计的一个有吸引力的靶点。通过在先导化合物的结构上引入亲水性哌嗪基团和疏水性丙酰基片段，得到了对 sEH 具有皮摩尔水平抑制活性的化合物。显示出良好的微粒体稳定性、中等的血浆蛋白结合率、良好的口服生物利用度，并在大鼠中耐受良好。在 CFA 诱导的 CIA 小鼠中，具有显著的镇痛作用，改善了由 l-精氨酸诱导的急性胰腺炎中的胰腺损伤，逆转了胰腺损伤、水肿和中性粒细胞浸润，并增加了 LPS 诱导的败血症模型中 C57BL/6 小鼠的存活时间。此外，通过 Western blot 或酶联免疫吸附试验（ELISA）测定 sEH、COX-2、NOS-2、血管细胞黏附分子（VCAM）、IL-6、MCP-5 和肿瘤坏死因子α（TNF-α）的表达水平，均有不同程度的降低。这些结果表明，化合物是一种有前途的治疗关节炎、急性胰腺炎和败血症等炎症性疾病的候选药物。
