Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates
Substituted 2-thioxoimidazolidin-4-ones and imidazolidine-2,4-diones as fatty acid amide hydrolase inhibitors templates
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DOI：
10.1021/jm050977k
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发表时间：
2006-01-12
影响因子：
7.3
通讯作者：
Lambert, DM
中科院分区：
文献类型：
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作者：
Muccioli, GG;Fazio, N;Lambert, DM
脂肪酸酰胺水解酶（FAAH）在水解内源性生物活性脂肪酸衍生物中的重要作用的证明已经启动了对该酶抑制剂的探索。沿着这条线，一组58咪唑烷-2,4-二酮和2-硫代吡唑烷-4- 1衍生物被评价为FAAH抑制剂。在这些化合物中，3-取代5,5'-二烯基咪唑烷-2,4-二酮和3-取代5,5'-二苯基-2-硫代咪唑烷-4-酮衍生物先前被描述为CB，大麻素受体配体。在本研究中，我们合成了几种具有有趣的FAAH抑制活性的衍生物，并且对CB和CB大麻素受体没有亲和力。例如，3-庚基-5,5′-二苯基咪唑烷-2,4-二酮（14）和5.5′-二苯基-3-十四烷基-2-硫代咪唑烷-4-酮（46）的pI（50）值分别为5.12和5.94。总之，尽管一些3-取代的5,5'-二苯基-2-硫代咪唑烷-4- 1和3-取代的5.5'-二苯基咪唑烷-2,4-二酮衍生物先前已被证明具有CB，大麻素受体配体的行为，但适当取代这些模板可导致FAAH抑制剂缺乏对大麻素受体的亲和力。
The demonstration of the essential role of fatty acid amide hydrolase (FAAH) in hydrolyzing endogenous bioactive fatty acid derivatives has launched the quest for the discovery of inhibitors for this enzyme. Along this line, a set of 58 imidazolidine-2,4-dione and 2-thioxoirnidazolidin-4-one derivatives was evaluated as FAAH inhibitors. Among these compounds, 3-substituted 5,5'-diplietiylimidazolidine-2,4-dione and 3-substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one derivatives were previously described as CB, cannabinoid receptor ligands. In the present study, we synthesized several derivatives exhibiting interesting FAAH inhibitory activity and devoid of affinity for the CB, and CB, cannabinoid receptors. For instance, 3-heptyl-5,5'-diphenylimidazolidine-2,4-dione (14) and 5.5'-diphenyl-3-tetradecyl-2-thioxo-imidazolidin-4-one (46) showed pI(50) values of 5.12 and 5.94, respectively. In conclusion, it appears that even though several 3-substituted 5,5'-diphenyl-2-thioxoimidazolidin-4-one and 3-substituted 5.5'-diphenylimidazolidine-2,4-dione derivatives have been previously shown to behave as CB, cannabinoid receptor ligands, appropriate substitutions of these templates can result in FAAH inhibitors devoid of affinity for the cannabinoid receptors.