Moser P, Sallmann A, Wiesenberg I
Chemistry and Biology Research Department, Ciba-Geigy Limited, Basel, Switzerland.
J Med Chem. 1990 Sep;33(9):2358-68. doi: 10.1021/jm00171a008.
The synthesis of a series of 2-anilinophenylacetic acids, close analogues of diclofenac, is described. These compounds were tested in two models used for evaluating the activity of nonsteroidal antiinflammatory drugs (NSAID's), inhibition of cyclooxygenase enzyme activity in vitro, and adjuvant-induced arthritis (AdA) in rats. Statistically significant correlations were found between the inhibitory activities of the compounds in these two models, indicating that cyclooxygenase inhibition seems to be the underlying mechanism for the antiinflammatory activity of these compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the crucial parameters for activity in both models were the lipophilicity and the angle of twist between the two phenyl rings. Optimal activities were associated with halogen or alkyl substituents in both ortho positions of the anilino ring. Compounds with OH groups in addition to two ortho substituents or compounds with only one or no ortho substituents were less active.
本文描述了一系列与双氯芬酸结构相近的2-苯胺基苯乙酸的合成。这些化合物在两种用于评估非甾体抗炎药（NSAID）活性的模型中进行了测试，即体外抑制环氧化酶活性以及大鼠佐剂性关节炎（AdA）模型。在这两种模型中，发现这些化合物的抑制活性之间存在统计学上的显著相关性，这表明环氧化酶抑制似乎是这些化合物抗炎活性的潜在机制。定量构效关系（QSAR）分析表明，两种模型中活性的关键参数是亲脂性以及两个苯环之间的扭转角。在苯胺环的两个邻位具有卤素或烷基取代基时活性最佳。除了两个邻位取代基外还带有羟基的化合物或仅具有一个邻位取代基或没有邻位取代基的化合物活性较低。
