新型塞来昔布衍生物的合成及其心血管风险的研究

Study on the synthesis of novel Celecoxib derivatives and the cardiovascular risk

目的通过改造塞来昔布结构,降低其心血管副作用。方法在塞来昔布-CF3位置进行修饰,合成4种新型衍生物;利用液质、核磁等方法进行表征、确定结构;用角叉菜胶诱导的足肿胀36只Wistar大鼠,按体重随机分为6组,塞来昔布组(灌胃给予塞来昔布),化合物1、化合物2、化合物3、化合物4组(灌胃给予化合物1~4)(每日给药剂量为5 mg/kg,药物分散到0.5 mL羧甲基纤维素钠水溶液中),对照组(每日给0.5 mL羧甲基纤维素钠水溶液)。用药3 d取各组大鼠血清用酶联免疫吸附试验(ELISA)法测定环氧合酶-2(COX-2)和炎性因子白细胞介素-6(IL-6)的表达水平,用药7 d取血浆测定凝血因子的变化。结果与塞来昔布组比较,化合物1组COX-2水平变化差异无统计学意义(P>0.05),化合物2~4组COX-2水平升高(P<0.05);与塞来昔布组比较,化合物1~4组IL-6水平变化差异无统计学意义(P>0.05);化合物2~4组凝血时间长于塞来昔布组(P<0.05)。结论化合物3和4在抑制炎性因子IL-6方面与塞来昔布相似的作用,但却对大鼠的凝血时间无明显的影响。因此,化合物3和4有望成为低心血管风险的塞来昔布衍生候选药物。

Objective To reduce the cardiovascular side effects of Celecoxib by modification structure.Methods Four novel derivatives of Celecoxib were synthesized via substitutions of Celecoxib-CF3 group.The structures were identified and determined by the data of LC-MS and NMR spectrum.A total of 36 Wistar rats with foot swelling induced by carrageen glue were randomly divided into 6 groups according to the weight,Celecoxib group(lavage given Celecoxib),compounds 1,2,3,4 group(gastric gavage compounds 1-4)(a daily dose of 5 mg/kg,drug dispersed to 0.5 mL carboxymethyl cellulose sodium),the control group(0.5 mL daily to sodium carboxy methyl cellulose)aqueous solution.Serum levels of cyclooxygenase-2(COX-2)and inflammatory factor interleukin-6(IL-6)were determined by enzyme-linked immunoadsorption assay(ELISA)on 3 days after treatment,and serum levels of clotting factors were determined on 7 days after treatment.Results Compared with Celecoxib group,there was no significant difference in COX-2 levels in the compound 1 group(P>0.05),while COX-2 levels in compound 2 to 4 group were increased(P<0.05).Compared with the Celecoxib group,there were no significant differences in IL-6 levels in the compounds 1 to 4 group(P>0.05).The clotting time of compounds 2 to 4 group was longer than that of celecoxib group(P<0.05).Conclusion Compounds 3 and 4 have similar effects to Celecoxib in inhibiting the inflammatory factor IL-6,however there is no significant effect on the clotting time of rats.Therefore,compounds 3 and 4 are expected to be Celecoxib-derived drug candidates with low cardiovascular risk.