a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
b Anhui Institute for Drug Control , Hefei , Anhui , P.R. China.
Pharm Biol. 2016 Nov;54(11):2505-2514. doi: 10.3109/13880209.2016.1160939. Epub 2016 Apr 21.
Development of a reliable and selective anti-inflammatory agent of cyclooxygenase-2 (COX-2), induced or up-regulated by inflammatory/injury stimulus such as IL-1β, TNF-α and LPS in the various types of organs, tissues and cells, with low side effects is a long-standing medicinal chemistry problem with significant social implications.
To target druggable enzymome COX-2 by exploiting NSAIDs and genipin (GEP) in anti-inflammatory infection.
The compound aspirin GEP ester (AGE) was designed by computer-assisted screening, synthesized in the esterification of the acylate derivative and the methylate derivative with EtN, and evaluated with 20, 40 and 60 mg/kg from days 18 to 24 after immunization in collagen-induced arthritis (CIA) rats by the sequential enzymatic experiments, western-blot analysis and pathological observation methods.
AGE exhibited higher binding affinity with COX-1 and displayed the lowest estimated free energy with COX-2 than other ligands built by hanging NSAIDs with GEP, and was characterized by H NMR, C NMR and HRMS. AGE was competed against COX-2 with molecule-dependent potencies and selectivity (IC: 0.36 mM; selectivity index: 275) in the sequential enzymatic experiments and decreased the expression of COX-2 in peripheral blood lymphocytes of CIA rats. AGE (40 and 60 mg/kg) could significantly relieve the secondary hind paw swelling and arthritis index, along with observing AGE attenuated histopathological changes of fibroblast like synovial tissue (FLST) and mesenteric lymph node lymphocytes (MLNL) in CIA rats.
AGE pharmacophore reported herein may be an effective strategy to develop a novel anti-inflammatory agent and potential inhibitor of COX-2.
开发一种可靠且选择性的环氧化酶-2（COX-2）抗炎剂，该抗炎剂由 IL-1β、TNF-α 和 LPS 等炎症/损伤刺激诱导或上调，在各种类型的器官、组织和细胞中具有低副作用，这是一个长期存在的药物化学问题，具有重要的社会意义。
利用非甾体抗炎药（NSAIDs）和京尼平（GEP）在抗炎感染中靶向可药物酶 COX-2。
通过计算机辅助筛选设计了化合物阿司匹林 GEP 酯（AGE），通过酯化酰基衍生物和甲酯衍生物与 EtN 合成，并在胶原诱导性关节炎（CIA）大鼠中，通过连续酶实验、western-blot 分析和病理观察方法，在免疫后第 18 至 24 天，用 20、40 和 60mg/kg 进行评价。
AGE 与 COX-1 具有更高的结合亲和力，与其他通过将 NSAIDs 与 GEP 悬挂而构建的配体相比，显示出 COX-2 的最低估计自由能，并用 1H NMR、13C NMR 和 HRMS 进行了表征。AGE 在连续酶实验中以分子依赖性的效力和选择性（IC：0.36mM；选择性指数：275）与 COX-2 竞争，并降低 CIA 大鼠外周血淋巴细胞中 COX-2 的表达。AGE（40 和 60mg/kg）可显著缓解继发性后爪肿胀和关节炎指数，同时观察到 AGE 减轻 CIA 大鼠纤维母细胞样滑膜组织（FLST）和肠系膜淋巴结淋巴细胞（MLNL）的组织病理学变化。
本文报道的 AGE 药效团可能是开发新型抗炎剂和 COX-2 潜在抑制剂的有效策略。
