Banoglu Erden, Okçelik Berna, Kupeli Esra, Unlü Serdar, Yeşilada Erdem, Amat Mercé, Caturla Joan F, Sahin M Fethi
Department of Pharmaceutical Chemistry, Division of Pharmaceutical Sciences, Faculty of Pharmacy, Gazi University, 06330 Etiler-Ankara, Turkey.
Arch Pharm (Weinheim). 2003 Jul;336(4-5):251-7. doi: 10.1002/ardp.200300723.
In this study, we have explored the prevention of gastric side effects such as gastric lesions and bleeding while maintaining the high analgesic and anti-inflammatory activities by the derivatization of the carboxylate moiety into amides in [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids. We have tested the analgesic and anti-inflammatory activities of the synthesized compounds in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. Compounds 3a, 3d, 3e, 3j and 3k potent analgesic and anti-inflammatory activities without gastric lesions in the tested animals. Therefore, conversion of the carboxylate moiety into certain amide derivatives generated potent analgesic and anti-inflammatory compounds while eliminating the gastrointestinal side effects. Cyclooxygenase (COX)-selectivity of the active compounds was also investigated by using in vitro human whole blood assay. Compounds 3a, 3e, 3h and 3k selective inhibition of COX-2 to some extent although the inhibitory activity was not very potent.
在本研究中，我们通过将[5-氯-6-(2-氯/氟苯甲酰基)-2-苯并恶唑啉酮-3-基]乙酸中的羧酸盐部分衍生化为酰胺，在保持高镇痛和抗炎活性的同时，探索了对胃病变和出血等胃部副作用的预防。我们分别通过对苯醌诱导的扭体试验和角叉菜胶诱导的后爪水肿模型，在体内测试了合成化合物的镇痛和抗炎活性。化合物3a、3d、3e、3j和3k在受试动物中具有强效镇痛和抗炎活性且无胃部病变。因此，将羧酸盐部分转化为某些酰胺衍生物可产生强效镇痛和抗炎化合物，同时消除胃肠道副作用。还通过体外人全血试验研究了活性化合物的环氧化酶(COX)选择性。化合物3a、3e、3h和3k在一定程度上对COX-2有选择性抑制作用，尽管抑制活性不是很强。
