Exceptionally potent inhibitors of fatty acid amide hydrolase: The enzyme responsible for degradation of endogenous oleamide and anandamide
Exceptionally potent inhibitors of fatty acid amide hydrolase: The enzyme responsible for degradation of endogenous oleamide and anandamide
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DOI：
10.1073/pnas.97.10.5044
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发表时间：
2000-05-09
影响因子：
11.1
通讯作者：
Cravatt, BF
中科院分区：
文献类型：
--
作者：
Boger, DL;Sato, H;Cravatt, BF
特别有效的脂肪酸酰胺水解酶（FAAH），负责降解油酰胺（内源性睡眠诱导脂质）和大麻素（大麻素受体的内源性配体）的酶的抑制剂的发展进行了详细说明。这些抑制剂可以作为有用的工具来阐明内源性油酰胺和花生四烯酸酰胺的作用，并且可以被证明是用于治疗睡眠障碍或疼痛的有用的治疗剂。几个特征的组合-最佳的C12-C8链长，在相应的花生四烯酰基δ（8，9）/δ（11，12）和油酰基δ（9，10）位置处的π-不饱和引入，和α-酮基N4恶唑吡啶，并结合第二弱碱性：氮提供FAAH抑制剂，其K（i）降至200 pM以下，并且比相应的三氟甲基酮的效力高10（2）-10（3）倍。
The development of exceptionally potent inhibitors of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid), and anandamide (an endogenous ligand for cannabinoid receptors) is detailed. The inhibitors may serve as useful tools to clarify the role of endogenous oleamide and anandamide and may prove to be useful therapeutic agents for the treatment of sleep disorders or pain. The combination of several features-an optimal C12-C8 chain length, pi-unsaturation introduction at the corresponding arachidonoyl Delta(8,9)/Delta(11,12) and oleoyl Delta(9,10) location, and an alpha-keto N4 oxazolopyridine with incorporation of a second weakly basic: nitrogen provided FAAH inhibitors with K(i)s that drop below 200 pM and are 10(2)-10(3) times more potent than the corresponding trifluoromethyl ketones.