Clemence F, Le Martret O, Delevallee F, Benzoni J, Jouanen A, Jouquey S, Mouren M, Deraedt R
Centre de Recherches Roussel Uclaf, Romainville, France.
J Med Chem. 1988 Jul;31(7):1453-62. doi: 10.1021/jm00402a034.
A series of 4-hydroxy-3-quinolinecarboxamides has been synthesized and evaluated by the oral route as antiinflammatory agents in carrageenin-induced foot edema and adjuvant-induced arthritis and as analgesic agents in the acetic acid induced writhing test. Among the most active molecules, some have shown both analgesic and acute antiinflammatory activities. Others, such as compounds 24, 37, and 52, were only powerful peripherally acting analgesics. Compound 52, being active at 1 mg/kg (ED50), is the most potent compound in the series. Some analogues, substituted in the 2-position by an alcohol, ester, or amine function, displayed potent antiarthritic activity in the same range as that of piroxicam and were also active in acute tests of inflammation and nociception. They inhibited the activity of both cyclooxygenase and 5-lipoxygenase at micromolar concentrations. Compound 102 (RU 43526) showed potent antiarthritic activity (adjuvant-induced arthritis, ED50 = 0.7 mg/kg, po) and gastrointestinal tolerance (ED100 greater than 250 mg/kg, po) and thus it is presently undergoing an extensive pharmacological evaluation.
已合成了一系列4-羟基-3-喹啉甲酰胺，并通过口服途径评估其作为角叉菜胶诱导的足肿胀和佐剂诱导的关节炎中的抗炎剂以及乙酸诱导的扭体试验中的镇痛剂的活性。在最具活性的分子中，一些分子同时显示出镇痛和急性抗炎活性。其他分子，如化合物24、37和52，只是强效的外周作用镇痛药。化合物52在1mg/kg时具有活性（ED50），是该系列中最有效的化合物。一些在2-位被醇、酯或胺官能团取代的类似物，在与吡罗昔康相同的范围内显示出强效的抗关节炎活性，并且在炎症和伤害感受的急性试验中也具有活性。它们在微摩尔浓度下抑制环氧化酶和5-脂氧合酶的活性。化合物102（RU 43526）显示出强效的抗关节炎活性（佐剂诱导的关节炎，ED50 = 0.7mg/kg，口服）和胃肠道耐受性（ED100大于250mg/kg，口服），因此目前正在进行广泛的药理学评估。
