Discovery of a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics
Discovery of a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics
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DOI：
10.1021/jm049614v
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发表时间：
2005-03-24
影响因子：
7.3
通讯作者：
Cravatt, BF
中科院分区：
文献类型：
--
作者：
Boger, DL;Miyauchi, H;Cravatt, BF
脂肪酸酰胺水解酶（FAAH）在其作用位点降解神经调节脂肪酸酰胺，包括大麻素（内源性大麻素激动剂）和油酰胺（睡眠诱导脂质），并密切参与其调节。在此，我们报告发现了一种强效、选择性和有效的可逆FAAH抑制剂，其在动物模型中产生镇痛作用，从而验证了疼痛干预的新治疗靶点。有用抑制剂发现的关键是针对丝氨酸水解酶超家族进行常规的蛋白质组学范围选择性筛选，确保对FAAH的选择性，并对候选抑制剂进行系统的体内检查。
Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.