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| Study on the synthesis of novel Celecoxib derivatives and the cardiovascular risk |
| LIN Shan1 WANG Zeyu2 YANG Jianfeng1 ZONG Ming1 FAN Yuhua1 LI Sen1▲ |
1.School of Pharmacy, Daqing Campus, Harbin Medical University, Heilongjiang Province, Daqing 163319, China;
2.Research Institute of Chinese Medicine, University of Macao, Macao Special Administrative Region, Taipa 999078, China |
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Abstract 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.
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