Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: Modulation at the N-portion of biphenyl-3-yl alkylcarbamates
Synthesis and quantitative structure-activity relationship of fatty acid amide hydrolase inhibitors: Modulation at the N-portion of biphenyl-3-yl alkylcarbamates
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DOI：
10.1021/jm701631z
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发表时间：
2008-06-26
影响因子：
7.3
通讯作者：
Piomelli, Daniele
中科院分区：
文献类型：
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作者：
Mor, Marco;Lodola, Alessio;Piomelli, Daniele
烷基氨基甲酸联苯-3-基酯是一类脂肪酸酰胺水解酶 (FAAH) 抑制剂，包含环己基氨基甲酸 3'-氨基甲酰基联苯-3-基酯 (URB597)，这是一种在大鼠和小鼠模型中具有镇痛、抗焦虑和抗抑郁作用的化合物。在这里，我们通过用一组选定的不同大小、形状、柔性和亲脂性的取代基替换母体化合物环己基氨基甲酸联苯-3-基酯 (URB524) (FAAH IC50 = 63 nM) 的环己基环，扩展了此类化合物的构效关系 (SAR)。对接实验和线性相互作用能 (LIE) 计算表明，O-芳基氨基甲酸酯的 N 末端基团适合底物结合位点的亲脂区域，模仿 anandamide 的花生四烯酰链。观察到 β-萘甲基衍生物 4q (IC50 = 5.3 nM) 及其 3'-氨基甲酰联苯-3-基酯 4z (URB880，IC50 = 0.63 nM) 的效力显着提高，表明形状互补性和氢键对于获得高效抑制剂至关重要。
Alkylcarbamic acid biphenyl-3-yl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors that comprises cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-yl ester (URB597), a compound with analgesic, anxiolytic-like and antidepressant-like properties in rat and mouse models. Here, we extended the structure-activity relationships (SARs) for this class of compounds by replacing the cyclohexyl ring of the parent compound cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) (FAAH IC50 = 63 nM) with a selected set of substituents of different size, shape, flexibility, and lipophilicity. Docking experiments and linear interaction energy (LIE) calculations indicated that the N-terminal group of O-arylcarbamates fits within the lipophilic region of the substrate-binding site, mimicking the arachidonoyl chain of anandamide. Significant potency improvements were observed for the beta-naphthylmethyl derivative 4q (IC50 = 5.3 nM) and its 3'-carbamoylbiphenyl-3-yl ester 4z (URB880, IC50 = 0.63 nM), indicating that shape complementarity and hydrogen bonds are crucial to obtain highly potent inhibitors.