Department of Toxicology, Unit of Medicinal Chemistry, University of Cagliari, via Ospedale 72, Cagliari I-09124, Italy.
J Med Chem. 2010 Mar 11;53(5):2286-98. doi: 10.1021/jm901891p.
Fatty acid amide hydrolase (FAAH) is the key hydrolytic enzyme for the endogenous cannabinoid receptor ligand anandamide. The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described. Structure-activity relationship studies indicated that the ester (33) with a 2-(4-(2-(trifluoromethyl)pyridin-4-ylamino)phenyl)acetic acid substituent was the most potent analogue in this series. The compound inhibited FAAH activity in a competitive manner with a K(i) value of 0.16 microM. The compound was also able to inhibit the FAAH activity in rat basophilic leukemia cells as assessed by measuring either the hydrolysis of anandamide, the FAAH-dependent cellular accumulation of anandamide, or the FAAH-dependent recycling of tritium to the cell membranes. The compound also inhibited the activity of monoacylglycerol lipase (MGL), the enzyme responsible for the hydrolysis of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol, with an IC(50) value of 1.9 microM. It is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.
脂肪酸酰胺水解酶（FAAH）是内源性大麻素受体配体花生四烯酸酰胺的关键水解酶。本文描述了一系列对乙酰氨基酚酯的合成和 FAAH 抑制活性评价。构效关系研究表明，具有 2-（4-（2-（三氟甲基）吡啶-4-基氨基）苯基）乙酸取代基的酯（33）是该系列中最有效的类似物。该化合物以竞争性方式抑制 FAAH 活性，K(i)值为 0.16 μM。该化合物还能够通过测量花生四烯酸的水解、FAAH 依赖性花生四烯酸在细胞内的积累或 FAAH 依赖性氚重新回收至细胞膜来抑制大鼠嗜碱性白血病细胞中的 FAAH 活性。该化合物还抑制单酰基甘油脂肪酶（MGL）的活性，MGL 是负责水解内源性大麻素受体配体 2-花生四烯酸甘油的酶，其 IC(50)值为 1.9 μM。结论是，该化合物可能是设计强效新型 FAAH 抑制剂的有用模板。
