1,2-diarylpyrroles as potent and selective inhibitors of cyclooxygenase-2
1,2-diarylpyrroles as potent and selective inhibitors of cyclooxygenase-2
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DOI：
10.1021/jm970036a
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发表时间：
1997-05-23
影响因子：
7.3
通讯作者：
Isakson, PC
中科院分区：
文献类型：
--
作者：
Khanna, IK;Weier, RM;Isakson, PC
已合成一系列 1,2-二芳基吡咯，并发现它们含有非常有效的选择性人类环氧合酶 2 (COX-2) 抑制剂。该论文描述了利用 Paal-Knorr 反应对目标分子进行简短而实用的合成。 1 上的亲电取代以区域选择性方式进行，该方法用于生成许多四取代的吡咯。通过芳环和吡咯环中取代基的修饰，研究了该系列的详细 SAR。二芳基吡咯 1 是一种非常有效（COX-2，IC50 = 60 nm）和选择性（COX-1/COX-2 = >1700）的抑制剂，而异构体 2 对 COX-2 完全没有活性。 1 中氟苯环上的取代基的修饰产生非常有效的 COX-2 抑制剂 (IC50 = 40-80 nm)，与 COX-1 相比具有优异的选择性 (1200 至 >2500)。含有磺酰胺基团的类似物 20 是一种优异的 COX-2 抑制剂，IC50 为 14 nm。吡咯环第 3 位含有 COCF3、SO2CF3 或 CH2OAr 等基团的四取代吡咯是优异的抑制剂（COX-2，IC50 = 30-120 nm）。在角叉菜胶诱导的大鼠爪水肿模型中进行的体内测试表明，1,2-二芳基吡咯是口服活性抗炎剂。化合物 3 是最有效的水肿抑制剂，ED50 为 4.7 mph。
Series of 1,2-diarylpyrroles has been synthesized and found to contain very potent and selective inhibitors of the human cyclooxygenase-2 (COX-2) enzyme. The paper describes short and practical syntheses of the target molecules utilizing the Paal-Knorr reaction. Electrophilic substitution on 1 proceeds in a regioselective fashion, and the method was used to generate a number of tetrasubstituted pyrroles. Detailed SAR on the series has been studied by modifications of the aryl rings and the substituents in the pyrrole ring. Diarylpyrrole 1 is a very potent (COX-2, IC50 = 60 nm) and selective (COX-1/COX-2 = >1700) inhibitor whereas the isomeric 2 is completely inactive against COX-2. Modifications of the substituents on the fluorophenyl ring in 1 yields very potent inhibitors of COX-2 (IC50 = 40-80 nm) with excellent selectivity (1200 to >2500) vs COX-1. Analog 20 containing a sulfonamide group is an excellent inhibitor of COX-2 with an IC50 of 14 nm. Tetrasubstituted pyrroles containing groups such as COCF3, SO2CF3, or CH2OAr at position 3 in the pyrrole ring give excellent inhibitors (COX-2, IC50 = 30-120 nm). In vivo testing in the carrageenan-induced paw edema model in the rat establishes that the 1,2-diarylpyrroles are orally active antiinflammatory agents. Compound 3 is the most potent inhibitor of edema with an ED50 of 4.7 mph.