Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)-2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.

中文翻译：

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探索布洛芬新型酰胺衍生物的脂肪酸酰胺水解酶和环氧合酶抑制特性。

脂肪酸酰胺水解酶（FAAH）的抑制作用可减少实验动物中非甾体抗炎药如舒林酸和消炎痛对胃肠道造成的损害，这表明FAAH环氧合酶（COX）双重作用抑制剂可能具有有用的治疗特性。在这里，我们研究了布洛芬的12种新型酰胺类似物作为潜在的双重作用FAAH / COX抑制剂。发现N-（3-溴吡啶-2-基）-2-（4-异丁基苯基）丙酰胺（Ibu-AM68）通过可逆的混合型抑制机制抑制大鼠脑匀浆[3H] anandamide的水解。 Ki值为0.26 µM，α值为4.9。浓度为10 µM时，该化合物不会抑制绵羊COX-1或人重组COX-2对花生四烯酸的环氧化作用。然而，此浓度的Ibu-AM68大大降低了COX-2催化内源性大麻素2-花生四烯酰甘油的环氧化作用的能力。结论是，Ibu-AM68是双作用FAAH /底物选择性COX抑制剂。