Novel Analgesic/Anti-Inflammatory Agents: Diarylpyrrole Acetic Esters Endowed with Nitric Oxide Releasing Properties
Novel Analgesic/Anti-Inflammatory Agents: Diarylpyrrole Acetic Esters Endowed with Nitric Oxide Releasing Properties
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DOI：
10.1021/jm200715n
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发表时间：
2011-11-24
影响因子：
7.3
通讯作者：
Anzini, Maurizio
中科院分区：
文献类型：
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作者：
Biava, Mariangela;Porretta, Giulio Cesare;Anzini, Maurizio
能够抑制环氧合酶（COX）并释放一氧化氮（NO）的化合物的设计应该会产生对胃肠道和心血管系统具有整体更安全特性的药物。在此，我们报道了一类新的吡咯衍生的硝基氧基酯（11a-j），环氧合酶-2（COX-2）选择性抑制剂，具有NO释放特性，目标是产生能够强烈抑制这种亚型并减少相关不良副作用的新分子。考虑到硝基氧基酯代谢转化为相应的醇，我们还研究了衍生物12a-j。所有化合物都被证明是非常有效和选择性的 COX-2 抑制剂；硝基氧基衍生物表现出有趣的离体 NO 依赖性血管舒张特性。选择化合物 11c、11d、12c 和 12d 进行进一步的体内研究，这些研究强调了良好的抗炎和镇痛活性。最后，在人全血 (HWB) 测定中测试的两种选定化合物（11c 和 12c）被证明是 COX-2 的优先抑制剂。
The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.